Quinuclidine derivatives and medicinal compositions containing the same

ABSTRACT

A compound of formula (I) is provided, wherein B, A, R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are as defined herein and X −  represents a pharmaceutically acceptable anion of a mono or polyvalent acid. Processes for the preparation of such compounds and pharmaceutical compositions containing them are also provided. group or a —CH 2 OH group; and X −  represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/250,447, filed Jun. 27, 2003, having a 371(c) filing date of Dec. 8,2003, which is a National Phase filing under 35 U.S.C. §371(c) ofInternational Patent Application No. PCT/EP01/15168, filed Dec. 20,2001, which claims priority to Spanish Application No. 200003130, filedDec. 28, 2000. The disclosures of which are herein incorporated byreference in their entirety.

This invention relates to new therapeutically useful quinuclidinederivatives, to some processes for their preparation and topharmaceutical compositions containing them.

The novel structures according to the invention are antimuscarinicagents with a potent and long lasting effect. In particular, thesecompounds show high affinity for muscarinic M3 receptors. This subtypeof muscarinic receptor is present in glands and smooth muscle andmediates the excitatory effects of the parasympathetic system onglandular secretion and on the contraction of visceral smooth muscle(Chapter 6, Cholinergic Transmission, in H. P. Rang et al.,Pharmacology, Churchill Livingstone, New York, 1995).

M3 antagonists are therefore known to be useful for treating diseasescharacterised by an increased parasympathetic tone, by excessiveglandular secretion or by smooth muscle contraction (R. M. Eglen and S.S. Hegde, (1997), Drug News Perspect., 10(8):462-469).

Examples of this kind of diseases are respiratory disorders such aschronic obstructive pulmonary disease (COPD), bronchitis, bronchialhyperreactivity, asthma, cough and rhinitis; urological disorders suchas urinary incontinence, pollakiuria, neurogenic or unstable bladder,cystospasm and chronic cystitis; gastrointestinal disorders such asirritable bowel syndrome, spastic colitis, diverticulitis and pepticulceration; and cardiovascular disorders such as vagally induced sinusbradycardia (Chapter 7, Muscarinic Receptor Agonists and Antagonists, inGoodman and Gilman's The Pharmacological Basis of Therapeutics, 10thedition, McGraw Hill, New York, 2001).

The compounds of the invention can be used alone or in association withother drugs commonly regarded as effective in the treatment of thesediseases. For example, they can be administered in combination withβ₂-agonists, steroids, antiallergic drugs, phosphodiesterase IVinhibitors an/or leukotriene D4 (LTD4) antagonists for simultaneous,separate or sequential use in the treatment of a respiratory disease.The claimed compounds are useful for the treatment of the respiratorydiseases detailed above in association with β₂-agonists, steroids,antiallergic drugs or phosphodiesterase IV inhibitors.

Compounds with related structures have been described asanti-cholinergic and/or anti-spasmodics agents in several patents.

For example, FR 2012964 describes quinuclidinol derivatives of theformula

in which R is H, OH or an alkyl group having 1 to 4 carbon atoms; R¹ isa phenyl or thienyl group; and R² is a cyclohexyl, cyclopentyl orthienyl group, or, when R is H, R¹ and R² together with the carbon atomto which they are attached, form a tricyclic group of the formula:

in which X is —O—, —S— or —CH₂—,or an acid addition or quaternary ammonium salt thereof.

In U.S. Pat. No. 4,465,834 a class of anticholinergic drugs having theformula

are described, in which R¹ is a carbocyclic or branched aliphatic groupof 3 to 8 carbon atoms (such as phenyl, cyclohexyl, cyclopentyl,cyclopropyl, cycloheptyl, and isopropyl), R² is a branched or linearaliphatic group containing 3 to 10 carbon atoms with 1 or 2 olefinic oracetylenic bonds, or is a phenylethinyl, a styryl, or an ethynyl group,and R³ is an alkyl or cyclic group of 4 to 12 carbon atoms containing atertiary amino nitrogen. The compounds of the invention are also claimedas either the free base or the acid-addition and quaternary ammoniumsalt forms thereof.

In U.S. Pat. No. 4,843,074 products of formula

are described, wherein X═H, halogen, lower alkyl, lower alkoxy, hydroxyand R=morpholinyl, thiomorpholinyl, piperidinyl,1,4-dioxa-8-azaspiro[4,5]decanyl, 4-(2,6-dimetylmorpholinyl),4-ketopiperidinyl, 4-hydroxypiperidinyl, 4-substituted piperazinyl. Thelower alkyl halide quaternary salts and pharmaceutically acceptable acidaddition salts are included in the invention.

U.S. Pat. No. 4,644,003 describes esters of 3-quinuclidinol of alphadisubstituted glicolic acids

and their pharmaceutically acceptable salts,

where R is phenyl, unsubstituted or substituted up to three substituentsincluding alkoxy, halogen, nitro, amino, alkylamino, dialkylamino,acylamino, and trifluoromethyl; and wherein R¹ is hydrogen, alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, alkyloxyalkyl,cycloalkyloxyalkyl, haloalkyl or haloalkenyl.

In WO 92/04346 are described compounds of formula

and their pharmaceutically acceptable salts, where X is a phenyl(optionally substituted) or a thienyl group and “Het” is either (a) afive membered nitrogen-containing heterocyclic group, (b) an oxadiazolylor thiadiazolyl group, or (c) a six membered nitrogen-containingheterocyclic group, and m is 1 or 2. (For a more detailed description,see the above mentioned publication)

Azoniabicyclic compounds of a general structure related to the compoundsof the invention are disclosed in WO 01/04118.

The present invention provides new quinuclidine ester derivatives withpotent antagonist activity at muscarinic M3 receptors which have thechemical structure described in formula (I):

wherein B is a phenyl ring, a 5 to 10-membered heteroaromatic groupcontaining one or more heteroatoms, or a naphthalenyl,5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, or biphenyl group;R¹, R² and R³ each independently represent a hydrogen or halogen atom,or a hydroxy group, a phenyl group, —OR⁷, —SR⁷, —NR⁷R⁸, —NHCOR⁷,—CONR⁷R⁸, —CN, —NO₂, —COOR⁷ or —CF₃ group, or a straight or branched,substituted or unsubstituted lower alkyl group, wherein R⁷ and R⁸ eachindependently represent a hydrogen atom, a straight or branched loweralkyl group, or together form an alicyclic ring; or R¹ and R² togetherform an aromatic or alicyclic ring or a heterocyclic group;n is an integer from 0 to 4;A represents a group selected from —CH₂—, —CH═CR⁹—, —CR⁹═CH—, —CR⁹R¹⁰—,—CO—, —O—, —S—, —S(O)—, —S(O)₂— and —NR⁹—, wherein R⁹ and R¹⁰ eachindependently represent a hydrogen atom, a straight or branched loweralkyl group, or together form an alicyclic ring;m is an integer from 0 to 8, provided that when m=0, A is not —CH₂—;p is an integer from 1 to 2 and the substitution in the azonia bicyclicring may be in the 2, 3 or 4 position including all possibleconfigurations of the asymmetric carbons;R⁴ represents a group of structure:

wherein R¹¹ represents a hydrogen or halogen atom, a hydroxy group, analkoxy group, a nitro group, a cyano group, —CO₂R¹² or —N^(R12R13)wherein R¹² and R¹³ are identical or different and are selected fromhydrogen and straight or branched lower alkyl groups, or a straight orbranched, substituted or unsubstituted lower alkyl group;R⁵ represents an alkyl group of 1 to 7 carbon atoms, an alkenyl groupcontaining 2 to 7 carbon atoms, an alkynyl group containing 2 to 7carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms, or a group offormula

wherein q=1 or 2 and R¹¹ is as defined above;R⁸ represents a hydrogen atom, a hydroxy group, a methyl group or a—CH₂OH group.The asymmetric carbon in the alpha position to the ester group, which issubstituted by R⁴, R⁵, and R⁶ may have R or S configuration.X⁻ represents a pharmaceutically acceptable anion of a mono orpolyvalent acid.

In the quaternary ammonium compounds of the present inventionrepresented by formula (I), an equivalent of an anion (X⁻) is associatedwith the positive charge of the N atom. X⁻ may be an anion of variousmineral acids such as, for example, chloride, bromide, iodide, sulfate,nitrate, phosphate, or an anion of an organic acid such as, for example,acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate,malate, mandelate, trifluoroacetate, methanesulfonate andp-toluenesulfonate. X⁻ is preferably an anion selected from chloride,bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinateor trifluoroacetate. More preferably X⁻ is chloride, bromide,trifluoroacetate or methanesulphonate.

The compounds of the present invention represented by the formula (I)described above, which may have one or more asymmetric carbons, includeall the possible stereoisomers. The single isomers and mixtures of theisomers fall within the scope of the present invention.

As used herein, an alkyl group is typically a lower alkyl group. A loweralkyl group preferably contains 1 to 8, preferably 1 to 6 and morepreferably 1 to 4 carbon atoms. In particular it is preferred that suchan alkyl group is represented by a methyl, ethyl, propyl, includingi-propyl, or butyl including a n-butyl, sec-butyl and tert-butyl group.An alkyl group containing 1 to 7 carbon atoms as mentioned herein, suchas that represented by R⁵, may be a C₁₋₄ alkyl group as mentioned aboveor a straight or branched pentyl, hexyl or heptyl group.

Optionally substituted lower alkyl groups mentioned herein includestraight or branched alkyl groups containing from 1 to 6, preferablyfrom 1 to 4, carbon atoms as mentioned above, which may be unsubstitutedor substituted in any position by one or more substituents, for exampleby 1, 2 or 3 substituents. When two or more substituents are present,each substituent may be the same or different. The substituent(s) aretypically halogen atoms or hydroxy or alkoxy groups, preferably hydroxyor alkoxy groups.

Alkenyl groups having 2 to 7 carbon atoms mentioned herein, such asthose represented by the group R⁵, are straight or branched groups suchas ethenyl, or straight or branched propenyl, butenyl, pentenyl, hexenylor heptenyl. The double bond may be in any position in the alkenylgroup, such as on the terminal bond.

Alkynyl groups having 2 to 7 carbon atoms mentioned herein, such asthose represented by the group. R⁵, are straight or branched groups suchas ethynyl, propynyl or straight or branched butynyl, pentynyl, hexynylor heptynyl. The triple bond may be in any position in the alkynylgroup, such as on the terminal bond.

Alkoxy groups mentioned herein, such as those that may be present in thegroup B, are typically lower alkoxy groups, that is groups containingfrom 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, thehydrocarbon chain being branched or straight. Preferred alkoxy groupsinclude methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy andt-butoxy.

Cycloalkyl groups and alicyclic groups mentioned herein, unlessotherwise specified, typically contain from 3 to 8 carbon atoms,preferably from 3 to 6 carbon atoms. Cycloalkyl groups and alicyclicrings of 3 to 6 carbon atoms include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. Cycloalkyl groups containing from 3 to 7carbon atoms include cycloalkyl groups of 3 to 6 carbon atoms andcycloheptyl.

The aromatic ring mentioned in relation to R¹ and R² typically containsfrom 5 to 14, preferably 5 to 10 carbon atoms. Examples of aromaticgroups include cyclopentadienyl, phenyl and naphthalenyl.

A heterocyclic or heteroaromatic group mentioned herein is typically a 5to 10 membered group, such as a 5, 6 or 7 membered group, containing oneor more heteroatoms selected from N, S and O. Typically, 1, 2, 3 or 4heteroatoms are present, preferably 1 or 2 heteroatoms. A heterocyclicor heteroaromatic group may be a single ring or two or more fused ringswherein at least one ring contains a heteroatom. Examples ofheterocyclic groups include piperidyl, pyrrolidyl, piperazinyl,morpholinyl, thiomorpholinyl, pyrrolyl, imidazolyl, imidazolidinyl,pyrazolinyl, indolinyl, isoindolinyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl,quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, quinuclidinyl,triazolyl, pyrazolyl, tetrazolyl and thienyl. Examples of heteroaromaticgroups include pyridyl, thienyl, furyl, pyrrolyl, imidazolyl,benzothiazolyl, pyridinyl, pyrazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl,phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl,triazolyl and pyrazolyl.

As used herein a halogen atom includes a fluorine, chlorine, bromine oriodine atom, typically a fluorine, chlorine or bromine atom.

Preferred compounds of formula (I) are those wherein B represents aphenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl,5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, imidazolyl orbenzothiazolyl group, in particular a phenyl, pyrrolyl, thienyl, furyl,biphenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl orbenzo[1,3]dioxolyl group such as a phenyl, thienyl or pyrrolyl group.

B may be unsubstituted or substituted with one, two or three groups (R¹to R³) which may be in any position on the ring. Typically it isunsubstituted or substituted with one group, for example when B is aphenyl group it may be substituted in the 2, 3 or 4 position. Typically,R¹, R² and R³ each independently represent a hydrogen or halogen atom,or a hydroxy, methyl, tert-butyl, —CH₂OH, 3-hydroxypropyl, —OMe, —NMe₂,—NHCOMe, —CONH₂, —CN, —NO₂, —COOMe or —CF₃ group, in particular ahydrogen, fluorine or chlorine atom or a hydroxy, methyl, —CH₂OH, —OMe,—NMe₂, —NHCOMe, —CONH₂, —CN, —NO₂, —COOMe or —CF₃ group. The mostpreferred groups R¹, R² and R³ are hydrogen, fluorine, chlorine orhydroxy.

Examples of substituted phenyl groups which may represent B are tolylincluding o-, m- and p-tolyl, 3-cyanophenyl, 2-, 3- and 4-hydroxyphenyland 2-, 3- and 4-fluorophenyl.

Preferred compounds of formula (I) are those wherein n=0 or 1; m is aninteger from 1 to 6, particularly 1, 2 or 3; and A represents a —CH₂—,—CH═CH—, —CO—, —NMe-, —O— or —S— group, in particular a —CH₂—, —CH═CH—,—O— or —S— group, for example a —CH₂—, —CH═CH— or —O— group.

More preferred salts of formula (I) are those wherein the azoniabicyclogroup is substituted on the nitrogen atom with a 3-phenoxypropyl,2-phenoxyethyl, 3-phenylallyl, phenethyl, 4-phenylbutyl, 3-phenylpropyl,3-(2-hydroxyphenoxy)propyl, 3-(4-fluorophenoxy)propyl, 2-benzyloxyethyl,3-pyrrol-1-ylpropyl, 2-thien-2-ylethyl, 3-thien-2-ylpropyl,3-phenylaminopropyl, 3-(methylphenylamino)propyl,3-phenylsulfanylpropyl, 3-o-tolyloxypropyl,3-(2,4,6-trimethylphenoxy)propyl,3-(2-tert-butyl-6-methylphenoxy)propyl, 3-(biphenyl-4-yloxy)propyl,3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)-propyl,3-(naphthalen-2-yloxy)propyl, 3-(naphthalen-1-yloxy)propyl,3-(2-chlorophenoxy)propyl, 3-(2,4-difluorophenoxy)propyl,3-(3-trifluoromethylphenoxy)propyl, 3-(3-cyanophenoxy)propyl,3-(4-cyanophenoxy)propyl, 3-(3-methoxyphenoxy)propyl,3-(4-methoxyphenoxy)propyl, 3-(benzo[1,3]dioxol-5-yloxy)propyl,3-(2-carbamoylphenoxy)propyl, 3-(3-dimethylaminophenoxy)propyl,3-(4-nitrophenoxy)propyl, 3-(3-nitrophenoxy)propyl,3-(4-acetylaminophenoxy)propyl, 3-(4-methoxycarbonylphenoxy)propyl,3-[4-(3-hydroxypropyl)phenoxy]propyl, 3-(2-hydroxymethylphenoxy)propyl,3-(3-hydroxymethylphenoxy)propyl, 3-(4-hydroxymethylphenoxy)propyl,3-(2-hydroxyphenoxy)propyl, 3-(4-hydroxyphenoxy)propyl,3-(3-hydroxyphenoxy)propyl, 4-oxo-4-thien-2-ylbutyl,3-(1-methyl-[1H]-imidazol-2-ylsulfanyl)propyl,3-(benzothiazol-2-yloxy)propyl, 3-benzyloxypropyl,6-(4-phenylbutoxy)hexyl, 4-phenoxybutyl, 4-(4-fluorophenyl)-4-oxobutylor 4-oxo-4-phenylbutyl group. Especially preferred salts are thosewherein the azoniabicyclo group is substituted on the nitrogen atom witha 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl,3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl, 3-(4-fluorophenoxy)propyl,3-thien-2-ylpropyl group, 4-oxo-4-thien-2-ylbutyl, 2-benzyloxyethyl,3-o-tolyloxypropyl, 3-(3-cyanophenoxy)propyl,3-(methylphenylamino)propyl, 3-phenylsulfanylpropyl,4-oxo-4-phenylbutyl, 3-(2-chlorophenoxy)propyl,3-(2,4-difluorophenoxy)propyl, 3-(4-methoxyphenoxy)propyl,3-(benzo[1,3]dioxol-5-yloxy)propyl. Examples of especially preferredsalts are those wherein the azoniabicyclo group is substituted on thenitrogen atom with a 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl,phenethyl, 3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl,3-(4-fluorophenoxy)propyl or 3-thien-2-ylpropyl group.

Further preferred compounds of formula (I) are those wherein R⁴represents a phenyl, 2-thienyl, 3-thienyl, 2-furyl or 3-furyl group. R¹¹preferably represents a hydrogen or halogen atom or an unsubstitutedlower alkyl group such as methyl or ethyl. Most preferably R¹¹ is ahydrogen atom. Therefore, for example, R⁴ may represent an unsubstitutedphenyl, 2-thienyl or 2-furyl group. Alternatively, R⁴ may represent anunsubstituted phenyl or 2-thienyl group. Preferably, R⁵ represents abenzyl, phenethyl, cyclopentyl, cyclohexyl, C₂₋₅ alkyl, C₂₋₅ alkenyl orC₂₋₅ alkynyl group, particularly a cyclopentyl, cyclohexyl, pentyl,allyl, vinyl, propynyl, phenethyl or benzyl group. Alternatively, R⁵represents a benzyl, cyclopentyl, cyclohexyl, C₂₋₅ alkyl, C₂₋₅ alkenylor C₂₋₅ alkynyl group, particularly a cyclopentyl, cyclohexyl, pentyl,allyl, vinyl, propynyl or benzyl group. The asymmetric carbon alpha tothe ester group, which is substituted by R⁴, R⁵ and R⁶ may have R or Sconfiguration.

Preferred compounds of formula (I) are those wherein the group—O—CO—C(R⁴)(R⁵)(R⁶) represents a group selected from2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy; 2,3-diphenylpropionyloxy;2-hydroxymethyl-2,3-diphenylpropionyloxy;2-hydroxy-2,3-diphenylpropionyloxy;2-hydroxy-3-phenyl-2-thien-2-ylpropionyloxy;2-hydroxy-2-thien-2-ylpent-4-enoyloxy;2-hydroxy-2-thien-2-ylheptanoyloxy;2-hydroxy-2-thien-2-ylpent-3-ynoyloxy;2-hydroxy-2-thien-2-ylbut-3-enoyloxy;2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy;2-cyclohexyl-2-hydroxy-2-phenylacetoxy;2-cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy,2-cyclopentyl-2-hydroxy-2-phenylacetoxy,2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy and2-hydroxy-4-phenyl-2-thien-2-ylbutanoyloxy. Examples of the group—O—CO—C(R⁴)(R⁵)(R⁶) are 2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy;2,3-diphenylpropionyloxy; 2-hydroxymethyl-2,3-diphenylpropionyloxy;2-hydroxy-2,3-diphenylpropionyloxy;2-hydroxy-3-phenyl-2-thien-2-ylpropionyloxy;2-hydroxy-2-thien-2-ylpent-4-enoyloxy;2-hydroxy-2-thien-2-ylheptanoyloxy;2-hydroxy-2-thien-2-ylpent-3-ynoyloxy;2-hydroxy-2-thien-2-ylbut-3-enoyloxy;2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy;2-cyclohexyl-2-hydroxy-2-phenylacetoxy and2-cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy.

In the most preferred embodiments of the invention p is 2, theazoniabicyclo[2.2.2]octane ring is substituted in the 3 position, andthis substituted carbon atom has (R)-configuration.

The following compounds are intended to illustrate but not to limit thescope of the present invention:

-   (3R)-3-(2,3-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-(2,3-Diphenylpropionyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2*)-2-Hydroxymethyl-2,3-diphenylpropionyloxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate (diastereomer 1)-   (3R)-3-[(2*)-2-Hydroxymethyl-2,3-diphenylpropionyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane    trifluoroacetate (diastereomer 1)-   (3R)-3-[(2*)-2-Hydroxymethyl-2,3-diphenylpropionyloxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate (diastereomer 2)-   (3R)-3-[(2*)-2-Hydroxymethyl-2,3-diphenylpropionyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane    trifluoroacetate (diastereomer 2)-   (3R)-3-[(2*)-2-Hydroxy-2,3-diphenylpropionyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    bromide (diastereomer 1)-   (3R)-3-[(2*)-2-Hydroxy-2,3-diphenylpropionyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane    bromide (diastereomer 1)-   (3R)-3-[(2*)-2-Hydroxy-2,3-diphenylpropionyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate (diastereomer 2)-   (3R)-3-[(2*)-2-Hydroxy-2,3-diphenylpropionyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate (diastereomer 2)-   (3R)-3-(2-Hydroxy-3-phenyl-2-thien-2-ylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-(2-Hydroxy-3-phenyl-2-thien-2-ylpropionyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    bromide-   (3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane    bromide-   (3R)-3-(2-Hydroxy-2-thien-2-ylheptanoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-(2-Hydroxy-2-thien-2-ylheptanoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-(2-Hydroxy-2-thien-2-ylpent-3-ynoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-(2-Hydroxy-2-thien-2-ylpent-3-ynoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-(2-Hydroxy-2-thien-2-ylbut-3-enoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-(2-Hydroxy-2-thien-2-ylbut-3-enoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    bromide-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane    bromide-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(4-oxo-4-thien-2-ylbutyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[4-(4-fluorophenyl)-4-oxobutyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(3-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   1-(2-Benzyloxyethyl)-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-o-tolyloxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   1-[3-(3-Cyanophenoxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(naphthalen-1-yloxy)propyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(methylphenylamino)propyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(2,4,6-trimethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   1-[3-(2-Chlorophenoxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(3-trifluoromethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   1-[3-(Biphenyl-4-yloxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(2,4-difluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-methoxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)propyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   1-[3-(Benzo[1,3]dioxol-5-yloxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   1-[3-(2-Carbamoylphenoxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(3-dimethylaminophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   1-[3-(4-Acetylaminophenoxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-methoxycarbonylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-hydroxymethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    bromide-   (3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   1-[3-(3-Cyanophenoxy)propyl]-(3R)-3-[(2S)-2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   1-[3-(3-Cyanophenoxy)propyl]-(3R)-3-[(2R)-2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3R)-3-(2-Hydroxy-4-phenyl-2-thien-2-ylbutanoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3S)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    bromide-   (3S)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   (3S)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   4-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate-   4-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane    trifluoroacetate    ((*): Configuration not assigned; either the (2R)- or the    (2S)-isomers of the above compounds may be produced).

The present invention also provides processes for preparing compounds offormula (I). The quaternary ammonium derivatives of general formula (I),may be prepared by reaction of an alkylating agent of general formula(II) with compounds of general formula (III). In formulae (I), (II) and(III), R¹, R², R³, B, A, X⁻, R⁴, R⁵, R⁶, n, m and p are as definedabove.

In formula (II), W represents any suitable leaving group, such as agroup X as defined above. Preferably, W represents a group X.

This alkylation reaction may be carried out by two differentexperimental procedures, a) and b) which are described above. Inparticular method b) provides a new experimental process, using solidphase extraction methodologies, that allows the parallel preparation ofseveral compounds. Methods a) and b) are described in the experimentalsection. If W represents a group other than X, the quaternary ammoniumsalt of formula (I) is produced from the product of method (a) or (b) bycarrying out an exchange reaction according to standard methods toreplace the anion W⁻ with the desired anion X⁻.

Compounds of general formula (II) which are not commercially availablehave been prepared by synthesis according to standard methods. Forexample, compounds wherein n=0 and A=—O—, —S— or —NR⁹—, wherein R⁹ is asdefined above, were obtained by reaction of the corresponding aromaticderivative or its potassium salt with an alkylating agent of generalformula Y—(CH₂)m-X, wherein X may be a halogen and Y may be a halogen ora sulphonate ester. In other examples, compounds of general formula(II), where n≧1 were synthesised from the corresponding alcoholderivative of general formula (IV) by known methods

wherein R¹, R², R³, n, m, and A are as defined above.

Compounds of general formula (III) may be prepared by different methods.These procedures are illustrated in the following schemes and detailedin the experimental section.

Method c)

Compounds of general formula (III) may be synthesised bytransesterification of a compound of formula (V) with a compound offormula (VI).

in which formulae R⁴, R⁵, R⁶ and p are as defined above and L representsa leaving group. For example L may be a chlorine atom, an imidazol-1-ylgroup, or a group —OR¹⁴ wherein R¹⁴ represents a straight or branched,substituted or unsubstituted lower alkyl group or a —COR¹⁵ group whereinR¹⁵ represents —COCR⁴R⁵R⁶. Typically L is —OR¹⁴ wherein R¹⁴ is methyl,ethyl or propyl, or L is an imidazol-1-yl group.Intermediates of formula (VI) may be prepared by standard methodsdescribed in the literature, for example as in FR 2012964.Method d)Compounds of formula (III) where R⁶ is a hydroxy group and p, R⁴ and R⁵are as described above, may also be prepared from the glyoxalate estersof general formula (VII) by reaction with the corresponding Grignardreagent.

Compounds of general formula (VII) may be prepared by standard methodsdescribed in the literature (WO 01/04118; WO 92/04346)

Method e)

Compounds of formula (III) where R⁶ is a group —CH₂OH, and p, R⁴ and R⁵are as described above, may also be prepared from the correspondingcompound of formula (III), where R⁶ is an hydrogen atom, by reactionwith formaldehyde in basic conditions. (Organic Syntheses CollectiveVolumes, VII, 271-274, (1990); WO 93/06098)

As will be described in the experimental part, the diastereomers of thecompounds of formula (III) may be separated by conventional methods, forexample by column chromatography or crystallisation.

The following compounds are compounds of general formula (III) whichhave not been described before:

compounds of formula (III)

wherein p, R4, R5 and R6 are as defined above, the substituent on theazabicyclo group is at position 3 or 4 and when it is at position 3 thissubstituted carbon has an enantiomerically pure R or S configuration,provided that when R4 is a 3-thienyl group and R5 is a cyclohexyl groupR6 is not a hydroxy group.

The substituent on the azabicyclo group is preferably at position 3 andmay have R or S configuration. The carbon substituted by R⁴, R⁵ and R⁶may have R or S configuration. The compound may be a single isomer.

Examples of the new compounds of formula (III) include:

-   (2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid    (3R)-1-azabicyclo[2.2.2]oct-3-yl ester ([α]²² _(D)=+19.7° (c=1,    CHCl₃)).-   (2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid    (3R)-1-azabicyclo[2.2.2]oct-3-yl ester ([α]²² _(D)=−14.2° (c=1,    CHCl₃)).-   (2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid    (3R)-1-azabicyclo[2.2.2]oct-3-yl ester ([α]²² _(D)=+21.1° (c=1,    CHCl₃)).-   (2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid    (3R)-1-azabicyclo[2.2.2]oct-3-yl ester ([α]²² _(D)=−23.5° (c=1,    CHCl₃)).-   (2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid    1-azabicyclo[2.2.2]oct-4-yl ester ([α]²² _(D)=−27.6° (c=1, CHCl₃)).

In particular:

-   (2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid    (3R)-1-azabicyclo[2.2.2]oct-3-yl ester ([α]²² _(D)=+19.7° (c=1,    CHCl₃)).-   (2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid    (3R)-1-azabicyclo[2.2.2]oct-3-yl ester ([α]²² _(D)=−14.2° (c=1,    CHCl₃)).-   (2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid    (3R)-1-azabicyclo[2.2.2]oct-3-yl ester ([α]²² _(D)=+21.10 (c=1,    CHCl₃)).-   (2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid    (3R)-1-azabicyclo[2.2.2]oct-3-yl ester ([α]²² _(D)=−23.5° (c=1,    CHCl₃)).

Compounds of formula (V) could be:

-   4-hydroxy-1-azabicyclo[2.2.1]heptane, described in WO93/15080-   4-hydroxy-1-azabicyclo[2.2.2]octane, described in Grob, C. A. et.    al. Helv. Chim. Acta (1958), 41, 1184-1190-   (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane or    (3S)-3-hydroxy-1-azabicyclo[2.2.2]octane, described in Ringdahl, R.    Acta Pharm Suec. (1979), 16, 281-283 and commercially available from    CU Chemie Uetikon GmbH.

The following examples are intended to illustrate, but not to limit, theexperimental procedures that have been described above.

The structures of the prepared compounds were confirmed by ¹H-NMR andMS. The NMR spectra were recorded using a Varian 300 MHz instrument andchemical shifts are expressed as parts per million (δ) from the internalreference tetramethylsilane. Their purity was determined by HPLC, usingreverse phase chromatography on a Waters instrument, with values greaterthan 95% being obtained. Molecular ions were obtained by electrosprayionization mass spectrometry on a Hewlett Packard instrument. Opticalrotations were obtained using a PERKIN-ELMER 241 MC Polarimeter.

METHOD -A- Example 13 Preparation of(3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide

250 mg (0.81 mmol) of 2-Hydroxy-2-thien-2-ylpent-4-enoic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester, Intermediate I-3, were dissolvedin 5 ml of acetonitrile and 7.5 ml of chloroform. To this solution wereadded 0.63 ml (4.1 mmol) of phenoxypropylbromide. After stirring for 48h at room temperature under a N₂ atmosphere, solvents were evaporated.Ether was added and the mixture stirred. The solid obtained was filteredand washed several times with ether. The yield was 0.3 g (71%) of thetitle compound as a mixture of diastereomers; mp: 157° C.

¹H-NMR (DMSO-d₆): δ 1.70-2.05 (m, 4H), 2.05-2.35 (m, 3H), 2.70-2.83 (m,1H), 2.90-3.02 (m, 1H), 3.25-3.60 (m, 7H), 3.82-3.97 (m, 1H), 3.97-4.10(m, 2H), 5.05-5.25 (m, 3H), 5.70-5.90 (m, 1H), 6.50 (d, 1H, OH),6.90-7.05 (m, 4H), 7.10-7.20 (m, 1H), 7.27-7.35 (m, 2H), 7.45 (m, 1H).

MS: [M-Br]⁺: 442.

METHOD -B- Example 35 Preparation of(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(naphthalen-1-yloxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

20 mg (0.06 mmols) of (2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylaceticacid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester (Intermediate I-15a), weredissolved in 1 ml of DMSO. To this solution 66 mg (0.30 mmol) of3-(naphthalen-1-yloxy)propyl chloride were added. After stirringovernight at room temperature, the mixture was purified by solid phaseextraction with a cation exchange Mega Bond Elut cartridge, previouslyconditioned at pH=7.5 with 0.1 M NaH₂PO4 buffer. The reaction mixturewas applied to the cartridge and washed first with 2 ml of DMSO and thenthree times with 5 ml of CH₃CN, rinsing away all starting materials. Theammonium derivative was eluted with 5 ml of 0.03 M TFA solution inCH₃CN:CHCl₃ (2:1). This solution was neutralized with 300 mg ofpoly(4-vinylpyridine), filtered and evaporated to dryness. The yield was10 mg (26%) of title compound.

¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.80-2.10 (m, 4H), 2.20-2.37 (m,3H), 2.75-2.92 (m, 1H), 3.20-3.65 (m, 7H), 3.90-4.05 (m, 1H), 4.15-4.30(m, 2H), 5.15-5.22 (m, 1H), 6.24 (s, 1H, OH), 6.95-7.05 (m, 2H),7.15-7.20 (m, 1H), 7.40-7.60 (m, 5H), 7.85-7.95 (m, 1H), 8.20-8.25 (m,1H).

MS: [M-CF₃COO]⁺: 520

The spatial configurations of the compounds of general formula (III)have been deduced from the configurations of their corresponding acids.These were determined either comparing the values of [α] obtained withthe values described in the literature or applying the CircularDichroism (CD) technique.

Since the CD curve of (2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid isknown (A. Tambuté and A. Collet, Bulletin de la Société Chimique deFrance, 1984, N° 1-2, pages II77 to II82) and all the acids evaluatedare structurally very similar to(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid, it can be assumed thatthe relative positions of the aryl, cycloalkyl, carboxyl and hydroxylsubstituents may be identified by comparison of their respective Δεvalues. The resulting configurations have been expressed as R or Saccording to Cahn-Ingol-Prelog system. (see TABLE 1)

The curves of CD spectra were recorded with a Jasco-720spectrophotometer (Software J-700) from 0.43 mM MeOH solutions of thesamples in 1 mm cells at 25° C.

TABLE 1 Circular Dichroism Compound [α]²² _(D) λ (nm) Δε (M⁻¹cm⁻¹)Configuration (+)-2-Cyclohexyl-2-hydroxy-2- +23.1° 224 +12.1 S^(a)phenylacetic acid (c = 1.4, EtOH) (−)-2-Cyclohexyl-2-hydroxy-2- −23.6°224 −11.7 R phenylacetic acid (c = 1.4, EtOH)(−)-2-Cyclopentyl-2-hydroxy-2-  −1.52° 224 −8.93 R^(b) phenylacetic acid(c = 3, MeOH) (+)-2-Cyclopentyl-2-hydroxy-2-  +6.63° 233 +4.18 Rthien-2-ylacetic acid^(c,1) (c = 1, EtOH) (−)-2-Cyclopentyl-2-hydroxy-2- −6.44° 233 −4.19 S thien-2-ylacetic acid^(c,2) (c = 1, EtOH)(−)-2-Cyclohexyl-2-hydroxy-2- −15.1° 235 −5.40 S thien-2-ylaceticacid^(c,3) (c = 1, EtOH) (+)-2-Cyclopentyl-2-fur-2-yl-2- +31.95° 230+7.64 S hydroxyacetic acid (c = 1, EtOH) (−)-2-Cyclopentyl-2-fur-2-yl-2-−32.10° 230 −7.44 R hydroxyacetic acid (c = 1, EtOH)(+)-2-Cyclohexyl-2-fur-2-yl-2- +40.9° 230 +10.9 S hydroxyacetic acid (c= 1, EtOH) (−)-2-Cyclohexyl-2-fur-2-yl-2- −39.7° 230 −10.8 Rhydroxyacetic acid (c = 1, EtOH) ^(a)A. Tambuté et A. Collet; Bulletinde la Societé Chimique de France, (1984), N°1-2, II-77-II-82:Configuration S assigned: [α]²⁴ _(D) = +25.2° (c = 1.4, EtOH), Δε =+12.9 M⁻¹cm⁻¹ (λ = 225 nm) ^(b)M. Mitsuya et al.; Bioorg. Med. Chem.,(1999), Vol 7, 2555-2567: Configuration R assigned [α]²⁰ _(D) = −1.9° (c= 3, MeOH) ^(c)E. Atkinson et al. J. Med. Chem., (1977), Vol 20, N° 12,1612-1617. The values for [α] were given (Configuration not assigned):c,1 and c,2: +51.3° and −51.0° (rotations observed at 350 nm (c = 2-5%,MeOH)),

METHOD -C-

Methyl ester derivatives of general formula (VI) were prepared bystandard methods described in the literature or following the proceduresdescribed in the examples: Intermediates I-9, I-10, I-11, I-12, I-13.

Intermediate I-1 Preparation of 2-Hydroxy-2-thien-2-ylheptanoic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

2.7 g of 2-Hydroxy-2-thien-2-ylheptanoic acid methyl ester (IntermediateI-9) (0.011 mol) were dissolved in 70 ml of toluene. To this solutionwere added 1.63 g (0.0128 mol) of(3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 0.18 g (0.0045 mol) of HNa(60% dispersion in mineral oil). The mixture was refluxed withcontinuous removal of distillate with replacement with fresh toluenewhen necessary for 1 hour. The cooled mixture was extracted with 1N HClacid, the aqueous layer washed with ether, basified with K₂CO₃ andextracted with CHCl₃. The organic layer was washed with water, driedover MgSO₄ and evaporated. The yield was 2.85 g (76%) of the titleproduct as a mixture of diastereomers, structure confirmed by ¹H-NMR.

¹H-NMR (CDCl₃): δ 0.80-0.95 (m, 3H), 1.20-1.40 (m, 6H), 1.40-1.90 (m,4H), 1.95-2.25 (m, 3H), 2.50-2.95 (m, 5H), 3.10-3.30 (m, 1H), 4.4 (bs,1H, OH), 4.82-4.94 (m, 1H), 6.94-7.02 (m, 1H), 7.06-7.14 (m, 1H),7.20-7.26 (m, 1H).

MS: [M+1]⁺: 338.

(Compound also prepared following method d)

Intermediate I-2 Preparation of 2,3-Diphenylpropionic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

Prepared using the same method as for Intermediate I-1, but from2,3-diphenylpropionic acid methyl ester. The yield was 1.71 g (61.5%) ofthe title product as a mixture of diastereomers.

¹H-NMR (DMSO): 1.05-1.20 (m, 1H), 1.30-1.60 (m, 3H), 1.65-1.75 (m, 1H),2.10-2.20 (m, 1H), 2.30-2.70 (m, 4H), 2.85-3.10 (m, 2H), 3.20-3.40 (m,1H), 3.95-4.10 (m, 1H), 4.50-4.65 (m, 1H), 7.10-7.45 (m, 10H).

MS: [M+1]⁺: 336

(2,3-diphenylpropionic acid methyl ester may be prepared from the2,3-diphenylpropionic acid, commercially available)

Intermediate I-3 Preparation of 2-Hydroxy-2-thien-2-ylpent-4-enoic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

Prepared using the same method as for Intermediate I-1, but from2-Hydroxy-2-thien-2-ylpent-4-enoic acid methyl ester (IntermediateI-10). The yield was 1.76 g (63.1%) of the title product as a mixture ofdiastereomers.

¹H-NMR (CDCl₃): δ 1.25-1.80 (m, 4H), 1.80-2.10 (m, 1H), 2.50-3.05 (m,7H), 3.10-3.35 (m, 2H), 4.55 (bs, 1H, OH), 4.75-4.95 (m, 1H), 5.10-5.30(m, 2H), 5.70-5.95 (m, 1H), 6.95-7.05 (m, 1H), 7.10-7.20 (m, 1H),7.20-7.30 (m, 1H).

MS: [M+1]⁺: 308

(Compound also prepared following method d)

Intermediate I-4 Preparation of 2-Cyclohexyl-2-fur-2-yl-2-hydroxyaceticacid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester

Prepared using the same method as for Intermediate I-1, but from 13.73 g(0.057 mol) of 2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid methyl ester(Intermediate I-11) dissolved in 350 ml of toluene, 8.6 g (0.067 mol) of(3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 1.37 g (0.0342 mol) of HNa(60% dispersion in mineral oil). The oil obtained (10.33 g) was purifiedby chromatography on silica gel eluting with chloroform/methanol/ammonia97:3:0.3. Appropriate fractions were combined and evaporated to obtainthe two diastereomers: I-4a and I-4b.

Intermediate I-4a (2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

1.59 g of an oil corresponding to the first eluted diastereomer wastriturated with a mixture of ethyl ether/isopropyl ether 1:1, to give0.82 g (8.6%, based on single isomer) of a solid whose structure wasconfirmed by ¹H-NMR as a pure diastereomer.

[α]²² _(D)=+21.1° (c=1, CHCl₃)).

¹H-NMR (CDCl₃): δ 1.10-1.45 (m, 8H), 1.45-1.60 (m, 2H), 1.60-1.85 (m,4H), 1.94-2.02 (m, 1H), 2.26-2.38 (m, 1H), 2.70-2.92 (m, 5H), 3.20-3.28(m, 1H), 3.78 (bs, 1H, OH), 4.90 (m, 1H), 6.30-6.40 (m, 2H), 7.40 (m,1H).

MS: [M+1]⁺: 334.

Intermediate I-4a was hydrolised (EtOH/NaOH 2N, 2 h r.t, 1 h 60° C.), toyield (+)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid: [α]²²_(D)=+40.9° (c=1, EtOH). Configuration S was assigned (See TABLE 1)

Intermediate I-4b (2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

1.12 g of an oil corresponding to the second eluted diastereomer wastriturated with a mixture of ethyl ether/isopropyl ether 1:1, to give0.57 g (6%, based on single isomer) of a solid whose structure wasconfirmed by ¹H-NMR as a pure diastereomer.

[α]²² _(D)=−23.5° (c=1, CHCl₃)).

¹H-NMR (CDCl₃): δ 1.10-1.50 (m, 8H), 1.50-1.90 (m, 6H), 2.04-2.12 (m,1H), 2.24-2.36 (m, 1H), 2.46-2.58 (m, 1H), 2.68-2.94 (m, 4H), 3.12-3.22(m, 1H), 3.77 (bs, 1H, OH), 4.90 (m, 1H), 6.40 (m, 2H), 7.42 (m, 1H)

MS: [M+1]⁺: 334.

Intermediate I-4b was hydrolised (EtOH/NaOH 2N, 2 h r.t, 1 h 60° C.), toyield (−)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid: [α]²²_(D)=−39.7° (c=1, EtOH).

Configuration R was assigned. (See TABLE 1)

Intermediate I-5 Preparation of 2-Cyclopentyl-2-hydroxy-2-phenylaceticacid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester

Prepared using the same method as for Intermediate I-1, but from 13.5 g(0.0576 mol) of 2-Cyclopentyl-2-hydroxy-2-phenylacetic acid methyl ester(commercially available) dissolved in 350 ml of toluene, 8.0 g (0.063mol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 0.91 g (0.023 mol)of HNa (60% dispersion in mineral oil). The yield was 13.1 g (69%) ofthe title product as an oil mixture of diastereomers, structureconfirmed by ¹H-NMR. The two diastereomers I-5a and I-5b were separatedafter several crystallizations.

Intermediate I-5a (2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

Several treatments of the oil mixture of diastereomers with differentmixtures of diethyl ether/hexane and diisopropyl ether/hexane (coolingat −60° C.) yield 4.3 g of a white solid identified by ¹H-RMN as anenriched diastereomer I-5a. This solid was recrystallised twice fromdiethyl ether/hexane (cooling at 0° C.) to yield 2 g (21%) of purediastereomer.

[α]²² _(D)=−10.8° (c=1, CHCl₃)

¹H-NMR (CDCl₃): δ 1.25-1.80 (m, 11H), 1.80-1.95 (m, 1H), 2.05-2.15 (m,1H), 2.40-2.50 (m, 1H), 2.62-3.05 (m, 5H), 3.05-3.18 (m, 1H), 3.80 (s,1H, OH), 4.85-4.90 (m, 1H), 7.22-7.42 (m, 3H), 7.60-7.75 (m, 2H).

Intermediate I-5a was hydrolised (EtOH/NaOH 2N, 2 h r.t. and 2 h at 60°C.) to give (−)-2-Cyclopentyl-2-hydroxy-2-phenylacetic acid as a pureenantiomer: [α]²² _(D)=−1.52° (c=3, MeOH). This value was assigned tothe R configuration provided that in the literature (M. Mitsuya et al.;Bioorg. Med. Chem., (1999), 7, 2555-2567) the R enantiomer has beendescribed with [α]²⁰ _(D)=−1.9° (c=3, MeOH). (See TABLE 1)

Intermediate I-5b (2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

The mother liquors from the first solid I-5a were evaporated and treatedwith maleic acid in isopropanol/diethyl ether. After cooling at 0-5° C.,7.0 g of a white solid were obtained and identified by ¹H-RMN as themaleate salt of a mixture enriched with the second diastereomer I-5b.After three crystallisations of this product from acetonitrile/diethylether (1:2.2), 2.4 g (18.7%, based on free base) of the maleate saltenriched with the second diastereomer I-5b (in a proportion 88:12 asdetermined by H-RMN) were obtained.

This maleate salt enriched with the second diastereomer I-5b (88:12) wastreated with CHCl₃ and K₂CO₃ solution to obtain the free base.

I-5b (Free Base):

[α]²² _(D)=+19.5° (c=1, CHCl₃)

¹H-NMR (CDCl₃): δ 1.20-1.80 (m, 12H), 1.85-2.0 (m, 1H), 2.60-3.05 (m,6H), 3.20-3.35 (m, 1H), 3.80 (s, 1H, OH), 4.75-4.82 (m, 1H), 7.20-7.45(m, 3H), 7.55-7.75 (m, 2H).

The signals corresponding to the diastereomer I-5a (12%) were observedat 2.05-2.15, 2.40-2.50, 3.05-3.18, 4.85-4.90 ppm.

Configuration S was assigned in view of the results obtained forIntermediate I-5a. (See TABLE 1).

Intermediate I-6 Preparation of2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

Prepared using the same method as for Intermediate I-1, but from 16.2 g(0.064 mol) of 2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic acid methylester (Intermediate I-12), dissolved in 400 ml of toluene, 9.5 g (0.074mol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 1.51 g (0.038 mol)of HNa (60% dispersion in mineral oil). The oil obtained (10.97 g) waspurified by chromatography on silica gel, eluting withchloroform/methanol/ammonia 95:5:0.5, to obtain 8.97 g of a pure productas a mixture of diastereomers, structure confirmed by ¹H-RMN. Threecrystallisations of this mixture from ethyl ether yield 1.68 g (15.2%)of a pure diastereomer (Intermediate I-6a). The mother liquors of thecrystallisations were enriched with the other diastereomer (IntermediateI-6b).

Intermediate I-6a (2S)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

[α]²² _(D)=−16.5° (c=1, CHCl₃).

¹H-NMR (CDCl₃): δ 1.05-1.85 (m, 13H), 1.85-2.0 (m, 1H), 2.0-2.16 (m,2H), 2.58-2.68 (m, 1H), 2.70-3.0 (m, 4H), 3.14-3.24 (m, 1H), 4.0 (s, 1H,OH), 4.90-5.0 (m, 1H), 6.95-7.05 (m, 1H), 7.10-7.15 (m, 1H), 7.20-7.30(m, 1H).

MS: [M+1]⁺: 350.

Intermediate I-6a was hydrolised (EtOH/NaOH 2N, 2 h r.t, 1 h 60° C.), toyield (−)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic acid: [α]²²_(D)=−15.1° (c=1, EtOH).

Configuration S was assigned. (See TABLE 1).

Intermediate I-6b (2R)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic acid(3R)-1-azabicyclo[2.2.2]oct-3(R)-yl ester

¹H-NMR (CDCl₃): δ 1.05-2.0 (m, 14H), 2.0-2.20 (m, 2H), 2.65-3.02 (m,5H), 3.24-3.36 (m, 1H), 4.0 (s, 1H, OH), 4.80-4.90 (m, 1H), 6.95-7.05(m, 1H), 7.10-7.20 (m, 1H), 7.20-7.30 (m, 1H).

The signals corresponding to the Intermediate I-6a (approx. 25%) wereobserved at 2.58-2.68, 3.14-3.24 and 4.90-5.0 ppm.

MS: [M+1]⁺: 350.

Configuration R was assigned in view of the results obtained withIntermediate I-6a. (See TABLE 1).

Intermediate I-7 (2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid(3S)-1-azabicyclo[2.2.2]oct-3-yl ester

510 mg (0.00225 mol) of (2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylaceticacid (obtained by hydrolysis of Intermediate I-15a) were dissolved in 7ml of DMF. This solution was stirred at room temperature and 638 mg(0.00393 mol) of 1,1′-carbonyldiimidazol were added in several portions.After 4.5 h the reaction mixture was cooled to 0° C. and 315 mg (0.00248mol) of (3S)-3-hydroxy-1-azabicyclo[2.2.2]octane and 83 mg (0.0021 mol)of HNa (60% dispersion in mineral oil) were added thereto. Afterstirring 112 h at room temperature the reaction mixture was treated withwater and extracted three times with diethyl ether. The organic layerswere combined, washed with brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography (eluent CHCl₃/MeOH 15:1) to obtain 360mg (47.6%) of the title product as an oil, structure confirmed by¹H-RMN.

[α]²² _(D)=−18.16° (c=1, CHCl₃)

¹H-NMR (CDCl₃): δ (Same description as in Intermediate I-15b)

MS: [M+1]⁺: 336.

Intermediate I-8 (2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid1-azabicyclo[2.2.2]oct-4-yl ester

Prepared using the same method as for Intermediate I-7, but from asolution of 660 mg (0.00282 mol) of(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid (obtained by hydrolysisof Intermediate I-16a) in 9 ml of DMF, 548 mg (0.00338 mol) of1,1′-carbonyldiimidazol, 394 mg (0.0031 mol) of4-hydroxy-1-azabicyclo[2.2.2]octane and 104 mg (0.00259 mol) of HNa (60%dispersion in mineral oil). After 44 h of stirring at room temperaturethe reaction mixture was treated with water and extracted three timeswith diethyl ether. The organic layers were combined, washed with brineand dried over anhydrous magnesium sulfate. The solvent was evaporatedand the residue was purified by silica gel column chromatography elutingwith CHCl₃ to CHCl₃/MeOH 15:1. The yield was 300 mg (31%) of the titleproduct.

[α]²² _(D)=−27.6° (c=1, CHCl₃)

¹H-NMR (CDCl₃): δ 1.0-1.55 (m, 7H), 1.55-1.75 (m, 2H), 1.75-1.85 (m,1H), 1.85-2.05 (m, 6H), 2.10-2.22 (m, 1H), 2.90-3.10 (m, 6H), 3.60-3.80(bs, 1H, OH), 7.20-7.40 (m, 3H), 7.57-7.67 (m, 2H).

MS: [M+1]⁺: 344.

Intermediate I-9 Preparation of 2-Hydroxy-2-thien-2-ylheptanoic acidmethyl ester

50 ml of a ether solution of 0.0338 mol of pentylmagnesium bromideprepared from 5.1 g of 1-bromopentane (0.0338 mol) and 0.0372 mols ofmagnesium, were added to a solution of 5 g of 2-oxo-2-thien-2-ylaceticacid methyl ester dissolved in 40 ml of a solution of ether/THF (50:50),at −70° C. under a N₂ atmosphere. The mixture was stirred at thistemperature for 10 minutes, and then warmed to room temperature. After16 h, the reaction mixture was treated with a saturated solution ofammonium chloride and extracted three times with ethyl acetate. Theorganic phases were combined, washed with water, and dried over MgSO₄.After removal of the solvent, the oil obtained was purified by columnchromatography (silica gel) using mixtures of hexane/AcOEt (25:1 to15:1) as eluent. The yield was 2.7 g (38%) of a pure product, whosestructure was confirmed by ¹H-NMR.

¹H-NMR (CDCl₃): δ 0.80-1.0 (m, 3H), 1.10-1.45 (m, 6H), 1.90-2.30 (m,2H), 3.80 (s, 3H), 4.05 (s, 1H, OH), 7.0 (m, 1H), 7.10 (m, 1H), 7.30 (m,1H).

(2-Oxo-2-thien-2-ylacetic acid methyl ester was prepared from thecommercially available 2-oxo-2-thien-2-ylacetic acid by a standardmethod).

Intermediate I-10 Preparation of 2-Hydroxy-2-thien-2-ylpent-4-enoic acidmethyl ester

Prepared using the same method as for Intermediate I-9. The yield was1.92 g. 45.3%.

¹H-NMR (CDCl₃): δ 2.75-3.0 (m, 2H), 3.80 (s, 3H), 4.0 (s, 1H, OH),5.10-5.30 (m, 2H), 5.70-5.90 (m, 1H), 6.95-7.05 (m, 1H), 7.10-7.20 (m,1H), 7.25-7.35 (m, 1H).

MS: [M]⁺=212.

Intermediate I-11 Preparation of 2-Cyclohexyl-2-fur-2-yl-2-hydroxyaceticacid methyl ester

Prepared using the same method as for Intermediate I-9, but from 73 ml(0.146 mol) of a solution of cyclohexylmagnesium chloride 2M in diethylether and 22.51 g (0.146 mol) of 2-fur-2-yl-2-oxoacetic acid methylester (dissolved in 330 ml of THF). The oil obtained was purified bycolumn chromatography (silica gel) using a mixture of hexane/AcOEt 9:1as eluent. After removal of the solvent 13.73 g (39%) of a pure productwere obtained whose structure was confirmed by MS and ¹H-NMR.

¹H-NMR (CDCl₃): δ 1.05-1.75 (m, 6H), 1.75-1.95 (m, 4H), 2.20-2.40 (m,1H), 3.80 (s, 3H), 3.95 (s, 1H, OH), 6.30-6.50 (m, 2H), 7.35-7.45 (m,1H).

MS: [M]⁺: 238.

(2-Fur-2-yl-2-oxoacetic acid methyl ester was prepared from thecommercially available 2-fur-2-yl-2-oxoacetic acid by a standardmethod).

Intermediate I-12 Preparation of2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic acid methyl ester

98.6 ml (0.197 mol) of a 2M solution of Cyclohexylmagnesium chloride indiethyl ether, were added to a solution of 27.97 g (0.164 mol) of2-oxo-2-thien-2-ylacetic acid methyl ester dissolved in 370 ml of THF,at −78° C. under a N₂ atmosphere. The mixture was stirred at thistemperature for 10 minutes, and then warmed to room temperature. After 1h, the reaction mixture was treated with a saturated solution ofammonium chloride and extracted three times with ethyl acetate. Theorganic phases were combined, washed with water, and dried over MgSO₄.After removal of the solvent, the oil obtained was purified by columnchromatography (silica gel) using hexane/AcOEt 90:10 as eluent. Theyield was 16.2 g (39.5%) of a pure product, whose structure wasconfirmed by ¹H-NMR.

¹H-NMR (CDCl₃): δ 1.0-1.55 (m, 6H), 1.55-1.90 (m, 4H), 2.0-2.20 (m, 1H),3.80 (s, 3H), 4.0 (s, 1H, OH), 7.0 (m, 1H), 7.10 (m, 1H), 7.20-7.30 (m,1H).

MS: [M⁺]: 254.

(Intermediate I-12 is described in E. Atkinson et al. J. Med. Chem.,(1977), Vol 20, N° 12, 1612-1617)

Intermediate I-13 Preparation of2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid methyl ester

Prepared as in Example I-12. The yield was 3.83 g (37%).

¹H-NMR (CDCl₃): δ 1.35-1.75 (m, 8H), 2.70-2.90 (m, 1H), 3.80 (s, 3H),4.02 (s, 1H, OH), 6.95-7.05 (m, 1H), 7.10-7.20 (m, 1H), 7.20-7.25 (m,1H).

(Intermediate I-13 is described in E. Atkinson et al. J. Med. Chem.,(1977), Vol 20, N° 12, 1612-1617)

METHOD -D- Intermediate I-14 Preparation of2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

Cyclopentylmagnesium chloride, 0.0472 mol (23.6 ml of a solution 2M inether) was added to a solution of 9.4 g (0.0377 mol) of2-fur-2-yl-2-oxoacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl esterdissolved in 125 ml of THF, at −70° C. under a N₂ atmosphere. Themixture was stirred at this temperature for 10 minutes, and then warmedto room temperature. After 16 h, the reaction mixture was treated with asaturated solution of ammonium chloride and extracted twice with ethylacetate. The organic phases were combined, washed with water, and driedover MgSO₄. After removal of the solvent, the oil obtained (7.5 g) waspurified by chromatography on silica gel eluting withchloroform/methanol/ammonia 95:5:0.5. Appropriate fractions werecombined and evaporated to obtain the two diastereomers: I-14a, I-14b

Intermediate I-14a (2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

1.55 g of an oil corresponding to the first eluted diastereomer wastriturated with a mixture of isopropyl ether/petroleum ether 1:1, togive 0.24 g (4%, based on single isomer) of a solid whose structure wasconfirmed by ¹H-NMR as a pure diastereomer; mp=109.6-110.6° C.

[α]²² _(D)=+19.7° (c=1, CHCl₃)

¹H-NMR (CDCl₃): δ 1.22-1.37 (m, 1H), 1.40-1.80 (m, 11H), 1.97 (m, 1H),2.74-2.96 (m, 6H), 3.19-3.30 (m, 1H), 3.80 (bs, 1H, OH), 4.85-4.89 (m,1H), 6.34-6.37 (m, 2H), 7.35 (m, 1H)

MS: [M+1]⁺=320.

Intermediate I-14a was hydrolised (EtOH/NaOH 2N, 2 h r.t.) to give(+)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid: [α]²² _(D)=+31.95°(c=1, EtOH). Configuration S was assigned. (See TABLE 1).

Intermediate I-14b (2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

1.10 g of a solid corresponding to the second eluted diastereomer wastriturated with a mixture of isopropyl ether/petroleum ether 1:1, togive 0.42 g (7%, based on single isomer) of a solid whose structure wasconfirmed by ¹H-NMR as a pure diastereomer; mp=119.9-122.1° C.

[α]²² _(D)=−14.20 (c=1, CHCl₃)

¹H-NMR (CDCl₃): δ 1.40-1.90 (m, 12H), 2.07 (m, 1H), 2.49-2.56 (m, 1H),2.67-2.86 (m, 5H), 3.12-3.24 (m, 1H), 3.80 (bs, 1H, OH), 4.87-4.91 (m,1H), 6.35-6.39 (m, 2H), 7.38 (m, 1H)

MS: [M+1]⁺=320

Intermediate I-14b was hydrolised (EtOH/NaOH 2N, 2 h r.t.) to give(−)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid: [α]²² _(D)=−32.10°(c=1, EtOH).

Configuration R was assigned. (See TABLE 1).

(2-Fur-2-yl-2-oxoacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester maybe prepared as described in WO 01/04118)

Intermediate I-15 Preparation of2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

Prepared using the same method as for Intermediate I-14, but from 20.8 g(0.0784 mol) of 2-oxo-2-thien-2-ylacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester and cyclopentylmagnesiumchloride, 0.08 mol (40 ml of a solution 2M in ether). The oil obtained(15.64 g) was purified by chromatography on silica gel eluting withchloroform/methanol/ammonia 97:3:0.5 to obtain 8.38 g (32%) of a pureproduct, mixture of diastereomers: I-15a and I-15b. Structure confirmedby ¹H-NMR.

Intermediate I-15a (2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

The oil mixture of diastereomers was treated with isopropyl ether toobtain a solid, that was treated again with isopropyl ether to yield 2.2g of a pure diastereomer (Intermediate I-15a, 16.7% based on a singleisomer).

[α]²² _(D)=−5.75° (c=1, CHCl₃); mp: 152-157° C.

¹H-NMR (CDCl₃): δ 1.40-1.80 (m, 11H), 1.80-2.0 (m, 1H), 2.10 (m, 1H),2.52-2.65 (m, 1H), 2.70-2.95 (m, 5H), 3.10-3.22 (m, 1H), 4.07 (s, 1H,OH), 4.85-4.95 (m, 1H), 6.95-7.05 (m, 1H), 7.10-7.20 (m, 1H), 7.20-7.27(m, 1H).

MS: [M+1]⁺=336

Intermediate I-15a was hydrolised (EtOH/NaOH 2N, 2 h r.t. and 2 h at 60°C.) to give (−)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid: [α]²²_(D)=−6.44° (c=1, EtOH).

Configuration S was assigned. (See TABLE 1).

Intermediate I-15b (2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

The mother liquors of the first crystallization of intermediate I-15awere evaporated, and the oil obtained treated with isopropyl ether togive a solid, that was treated again with isopropyl ether to yield 1.47g of the second diastereomer intermediate I-15b (11.2% based on singleisomer).

[α]²² _(D)=+22.49° (c=1, CHCl₃); mp: 99-102° C.

¹H-NMR (CDCl₃): δ 1.25-1.85 (m, 12H), 2.0 (m, 1H), 2.65-2.95 (m, 6H),3.22-3.34 (m, 1H), 4.05 (s, 1H, OH), 4.80-4.92 (m, 1H), 6.90-7.0 (m,1H), 7.10-7.16 (m, 1H), 7.20-7.27 (m, 1H).

MS: [M+1]⁺=336

Intermediate I-15b was hydrolised (EtOH/NaOH 2N, 2 h r.t. and 2 h at 60°C.) to give (+)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid: [α]²²_(D)=+6.63° (c=1, EtOH).

Configuration R was assigned. (See TABLE 1).

(Intermediates I-15a and I-15b have also been prepared following methodc)

(2-Oxo-2-thien-2-ylacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl estermay be prepared as described in WO 01/04118)

Intermediate I-16 Preparation of 2-Cyclohexyl-2-hydroxy-2-phenylaceticacid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester

Cyclohexylmagnesium chloride, 0.127 mol (63.6 ml of a solution 2M inether), was added to a solution of 28.7 g (0.111 mol) of2-oxo-2-phenylacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl esterdissolved in 350 ml of THF, at −70° C. under a N₂ atmosphere. Themixture was stirred at this temperature for 10 minutes, and then warmedto room temperature. After 1 h, the reaction mixture Was treated with asaturated solution of ammonium chloride and extracted twice with ethylacetate. The organic phases were combined, washed with water, and driedover MgSO₄. After removal of the solvent, the oil obtained (27.0 g) waspurified by chromatography on silica gel eluting withchloroform/methanol 10:1. The yield was 18.7 g (49.2%) of a pureproduct, mixture of diastereomers: I-16a and I-16b.

Intermediate I-16a (2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

16 g of the oil mixture of diastereomers were dissolved in isopropanoland treated with 5.4 g of fumaric acid. After cooling to 0-5° C., 8 g ofthe fumarate salt of the first diastereomer (Intermediate I-16a) wereobtained.

Fumarate salt: MS: [M (free base)+1]⁺=344.

The 8 g of this salt were recrystallised from isopropanol to obtain 5 gof a more pure product. This salt was treated with CHCl₃ and K₂CO₃solution to obtain the free base Intermediate I-16a.

I-16a (free base):

[α]²² _(D)=−14.9° (c=1, CHCl₃).

¹H-NMR (CDCl₃): δ 1.0-1.95 (m, 14H), 2.04-2.12 (m, 1H), 2.16-2.32 (m,1H), 2.38-2.50 (m, 1H), 2.64-2.96 (m, 4H), 3.04-3.16 (m, 1H), 3.70-3.85(s, 1H, OH), 4.85-4.90 (m, 1H), 7.25-7.40 (m, 3H), 7.60-7.70 (m, 2H).

Intermediate I-16a (free base) was hydrolised (EtOH/NaOH 2N, 7 h at 60°C.) to give (−)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid as a pureenantiomer [α]²² _(D)=−23.6° (c=1.4, EtOH). This value was assigned tothe R configuration provided that in the literature (A. Tambuté, A.Collet; Bulletin de la Société Chimique de France, 1984, N° 1-2, pagesII-77 to II-82) the (2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid hasbeen described with [α]²⁴ _(D)=+25.20 (c=1.4, EtOH). (See TABLE 1).

Intermediate I-16b (2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

The mother liquors of the fumarate salt of the Intermediate I-16a wereevaporated and the residue dissolved in water. The obtained solution waswashed with ether, basified with K₂CO₃ and extracted with CHCl₃. Theorganic layer was dried over MgSO₄ and the solvent was evaporated. Theoil obtained (7.5 g) was dissolved in 50 ml of isopropanol and treatedwith EtOH/HCl(g) After the addition of 75 ml of ethyl ether, 3.1 g ofthe chlorhydrate salt of the second diastereomer, Intermediate I-16b,were obtained.

Chlorhydrate salt: MS: [M (free base)+1]⁺=344.

The chlorhydrate salt was treated with CHCl₃ and K₂CO₃ solution toobtain the free base Intermediate I-16b.

I-16b (free base):

[α]²² _(D)=+25.30 (c=1, CHCl₃).

¹H-NMR (CDCl₃): δ 1.0-1.78 (m, 13H), 1.78-1.90 (m, 1H), 1.92-2.0 (m,1H), 2.20-2.34 (m, 1H), 2.66-2.96 (m, 5H), 3.20-3.32 (m, 1H), 3.70-3.85(s, 1H, OH), 4.75-4.85 (m, 1H), 7.25-7.40 (m, 3H), 7.60-7.70 (m, 2H).

Intermediate I-16b (free base) was hydrolised (EtOH/NaOH 2N, 60° C., 8h) to give (+)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid as a pureenantiomer. [α]²² _(D)=+23.1° (c=1.4, EtOH). This value was assigned tothe S configuration according with the results obtained withIntermediate I-16a. (See TABLE 1).

(2-Oxo-2-phenylacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester may beprepared as described in WO 92/04346.)

Intermediate I-17 2-hydroxy-2,3-diphenylpropionic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

Prepared using the same method as for Intermediate I-16 as a mixture ofdiastereomers I-17a and I-17b, which were separated by crystallisationusing ether/isopropyl ether.

Intermediate I-17a (2*)-2-hydroxy-2,3-diphenylpropionic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester,

First Diastereomer Obtained.

The yield was 0.87 g (42.6% based on single isomer), mp: 132° C.

¹H-NMR (CDCl₃): δ 1.30-1.60 (m, 2H), 1.60-1.90 (m, 2H), 2.05 (m, 1H),2.20-2.35 (m, 1H), 2.50-2.90 (m, 4H), 3.0-3.15 (m, 1H), 3.25 and 3.60(dd, 2H), 3.70 (bs, 1H, OH), 4.70-4.80 (m, 1H), 7.15-7.45 (m, 8H),7.65-7.75 (m, 2H).

MS: [M+1]⁺=352

((*): Configuration not assigned)

Intermediate I-17b (2*)-2-hydroxy-2,3-diphenylpropionic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester,

Second Diastereomer Obtained.

The yield was 0.23 g (11.2% based on single isomer), mp: 107° C.

¹H-NMR (CDCl₃): δ 1.20-1.35 (m, 1H), 1.35-1.55 (m, 2H), 1.55-1.70 (m,1H), 1.80-1.95 (m, 1H), 2.55-2.90 (m, 5H), 3.10-3.20 (m, 1H), 3.25 and3.60 (dd, 2H), 3.80 (bs, 1H, OH), 4.65-4.80 (m, 1H), 7.20-7.50 (m, 8H),7.65-7.75 (m, 2H).

MS: [M+1]⁺=352

((*): Configuration not assigned)

Intermediate I-18 2-Hydroxy-3-phenyl-2-thien-2-ylpropionic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

Prepared using the same method as for Intermediate I-15 as a mixture ofdiastereomers. The yield was 0.81 g (54%). The product was purified bypreparation of the chlorhydrate salt, 0.57 g of this salt were obtained(63% from the free base).

Chlorhydrate salt:

¹H-NMR (DMSO-d₆): δ 1.40-1.60 (m, 1H), 1.60-1.95 (m, 3H), 2.05 and 2.10(m, 1H), 2.75-3.65 (m, 8H), 4.90-5.05 (m, 1H), 6.50 and 6.55 (s, 1H,OH), 6.95-7.05 (m, 1H), 7.10-7.30 (m, 6H), 7.40-7.50 (m, 1H), 10.9 (bs,1H, NH⁺).

MS: [M+1]⁺=358

Intermediate I-19 2-Hydroxy-2-thien-2-ylpent-3-ynoic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

Prepared using the same method as for Intermediate I-15 as a mixture ofdiastereomers. The yield was 1.88 g (25.6%)

¹H-NMR (CDCl₃): δ 1.20-1.90 (m, 4H), 1.92 and 1.96 (s, 3H, CH3), 2.0 and2.16 (m, 1H), 2.45-2.90 (m, 5H), 3.05-3.20 and 3.15-3.27 (m, 1H),4.85-4.92 (m, 1H), 6.94-7.0 (m, 1H), 7.24-7.30 (m, 2H), the signal forOH group is observed between 4.5 and 5.5 as a broad band.

MS: [M+1]⁺=306

Intermediate I-20 2-Hydroxy-2-thien-2-ylbut-3-enoic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

Prepared using the same method as for Intermediate I-15 as a mixture ofdiastereomers. The yield was 1.74 g (18.8%)

¹H-NMR (CDCl₃): δ 1.30-1.90 (m, 4H), 2.05-2.15 (m, 1H), 2.60-3.0 (m,5H), 3.15-3.35 (m, 1H), 3.40-4.70 (broad band, 1H, OH), 4.85-4.95 (m,1H), 5.30-5.40 (m, 1H), 5.60-5.75 (m, 1H), 6.30-6.50 (m, 1H), 6.95-7.05(1H), 7.10-7.15 (m, 1H), 7.25-7.30 (m, 1H).

MS: [M+1]⁺=294

Intermediate I-21 2-Hydroxy-4-phenyl-2-thien-2-ylbutyric acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

Prepared using the same method as for Intermediate I-15 as a mixture ofdiastereomers. The yield was 0.29 g (2.4%).

¹H-NMR (CDCl₃): δ 1.25-1.95 (m, 4H), 1.95-2.10 (m, 1H), 2.30-3.0 (m,9H), 3.10-3.25 (m, 1H), 4.80-4.90 (m, 1H), 6.95-7.05 (m, 1H), 7.05-7.40(m, 7H).

MS: [M+1]⁺=372

METHOD -E- Intermediate I-22 Preparation of2-Hydroxymethyl-2,3-diphenylpropionic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

Lithium diisopropylamide (0.0048 mol) 2.40 ml of a 2M solution (inheptane/THF/ethylbenzene) was added to a stirred solution of 1.5 g(0.0045 mol) of 2,3-diphenylpropionic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester in 30 ml of THF at −70° C. undera N₂ atmosphere. CH₂O (gas) was bubbled into the reaction mixture via asteady stream of dry N₂ during 10 min at −70° C. and then while themixture was warmed at room temperature. The reaction was quenched byaddition of saturated ammonium chloride solution (100 ml) and theresultant mixture was extracted twice with 100 ml of ethyl acetate. Theorganic layers were combined, dried over MgSO₄ and evaporated to yield1.9 g of an oil. This 1.9 g were combined with 3.28 g of a previouspreparation and the product obtained (5.18 g) was purified bychromatography on silica gel eluting with chloroform/methanol/ammoniafrom 97.5:2.5:0.25 to 90:10:1. Appropriate fractions were combined andevaporated to obtain the two diastereomers: Intermediates I-22a andI-22b

Intermediate I-22a (2*)-2-Hydroxymethyl-2,3-diphenylpropionic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

1.25 g of a solid corresponding to the first eluted diastereomer wastriturated with isopropyl ether, to give 0.95 g (42%, based on singleisomer) of a white solid whose structure was confirmed by ¹H-NMR as apure diastereomer; mp: 119° C.

¹H-NMR (CDCl₃): δ 1.20-1.35 (m, 1H), 1.40-1.70 (m, 3H), 1.90 (m, 1H),2.5 (bs, OH), 2.60-2.85 (m, 5H), 3.15-3.25 (m, 1H), 3.40-3.50 (dd, 2H),3.95-4.10 (dd, 2H), 4.85 (m, 1H), 7.05 (m, 2H), 7.15-7.40 (m, 8H)

MS: [M+1]⁺=366

((*): Configuration not assigned)

Intermediate I-22b (2*)-2-Hydroxymethyl-2,3-diphenylpropionic acid(3R)-1-azabicyclo[2.2.2]oct-3-yl ester

1.84 g of an oil corresponding to the second eluted diastereomer waspurified by column chromatography (in the above described conditions) toyield 1.26 g of a solid that after trituration with isopropyl etheryield 0.95 g of a white solid whose structure was confirmed by ¹H-NMR asa pure diastereomer (42%, based on single isomer); mp: 154° C.

¹H-NMR (CDCl₃): δ 1.20-1.35 (m, 1H), 1.50-1.75 (m, 3H), 2.0 (m, 1H),2.35 (bs, OH), 2.50-2.80 (m, 5H), 3.10-3.20 (m, 1H), 3.35-3.50 (dd, 2H),3.95-4.10 (dd, 2H), 4.85 (m, 1H), 7.0 (m, 2H), 7.15-7.40 (m, 8H).

MS: [M+1]⁺=366

((*): Configuration not assigned)

Also included within the scope of the present invention arepharmaceutical compositions which comprise, as the active ingredient, atleast one quinuclidine derivative of general formula (I) in associationwith a pharmaceutically acceptable carrier or diluent. Preferably thecomposition is made up in a form suitable for oral administration.

The pharmaceutically acceptable carrier or diluents which are mixed withthe active compound or compounds, to form the composition of thisinvention are well-known per se and the actual excipients used dependinter alia on the intended method of administration of the composition.

Compositions of this invention are preferably adapted for oraladministration. In this case, the composition for oral administrationmay take the form of tablets, film-coated tablets, liquid inhalant,powder inhalant and inhalation aerosol; all containing one or morecompounds of the invention; such preparations may be made by methodswell-known in the art.

The diluents which may be used in the preparations of the compositionsinclude those liquid and solid diluents which are compatible with theactive ingredient, together with colouring or flavouring agents, ifdesired. Tablets or film-coated tablets may conveniently contain between1 and 500 mg, preferably from 5 to 300 mg of active ingredient. Theinhalant compositions may contain between 1 μg and 1,000 μg, preferablyfrom 10 μg to 800 μg of active ingredient. In human therapy, the dose ofthe compound of general formula (I) depend on the desired effect andduration of treatment; adult doses are generally between 3 mg and 300 mgper day as tablets and 10 μg and 800 μg per day as inhalant composition.

Pharmacological Action

The results on human muscarinic receptors binding and in the test onbronchospasm in guinea pig, were obtained as described below.

Human Muscarinic Receptor Studies.

The binding of [3H]-NMS to human muscarinic receptors was performedaccording to Waelbroek et al (1990), Mol. Pharmacol., 38: 267-273.Assays were carried out at 25° C. Membrane preparations from stablytransfected chinese hamster ovary-K1 cells (CHO) expressing the genesfor the human muscarinic receptors M3 were used.

For determination of IC₅₀, membrane preparations were suspended in DPBSto a final concentration of 89 μg/ml for the M3 subtype. The membranesuspension was incubated with the tritiated compound for 60 min. Afterincubation the membrane fraction was separated by filtration and thebound radioactivity determined. Non specific binding was determined byaddition of 10⁻⁴ M atropine. At least six concentrations were assayed induplicate to generate individual displacement curves.

Our results show that the compounds of the present invention have highaffinities for muscarinic M3 receptors, preferably human muscarinicreceptors. Affinity levels have been measured by in vitro assays asdescribed above at 100 nM and 10 nM. Preferred compounds of theinvention produce an inhibition of [3H]-NMS binding of at least 35% at10 nM and of at least 65% at 100 nM (Table 2).

TABLE 2 % INHIBITION % INHIBITION concentration: concentration: N°COMPOUND 1,00E−07 M 1,00E−08 M Atropine 88.3 69.75 Ipratropium 93.7567.25 bromide 13 76 36 14 76.5 39.0 16 74.2 36.3 22 81.5 72 23 75.6 63.324 78 56.6 25 76.1 62.6 26 75.6 63.8 28 78.3 60.6 29 79.0 53.8 31 74.354.3 32 73.9 44.5 33 72.8 46.7 34 85.3 68.3 36 84.2 42.0 37 88.1 72.6 3886.3 57.7 40 86.9 72.7 43 83.4 58.7 44 84.6 44.6 46 87.1 57.6 53 81.5 5854 72.5 44.1 56 77.3 53.8 57 77.4 47.1 61 75.1 39.9 64 78.6 64.5 65 79.866.0 67 75.1 52.5 69 70.8 43.9 70 71.2 50.0 80 72.4 55.8 81 70.1 45.4 8270.6 55.3 83 72.7 60.3 84 68.3 41.0 86 68.2 37.2 88 65.5 35.7 89 68.551.3 92 69.4 49.2

Test on Bronchospasm in Guinea Pig

The studies were performed according to H. Konzett and F. Rössler(1940), Arch. Exp. Path. Pharmacol. 195: 71-74. Aqueous solutions of theagents to be tested were nebulized and inhaled by anaesthetizedventilated male guinea pigs (Dunkin-Hartley). Bronchial response tointravenous acetylcholine challenge was determined before and after drugadministration and the changes in pulmonary resistance at severaltime-points were expressed as percent of inhibition of bronchoespasm.

The compounds of the present invention inhibited the bronchospasmresponse to acetylcholine with high potency and a long duration ofaction.

From the above described results one of ordinary skill in the art canreadily understand that the compounds of the present invention haveexcellent antimuscarinic activity (M3) and thus are useful for thetreatment of diseases in which the muscarinic M3 receptor is implicated,including respiratory disorders such as chronic obstructive pulmonarydisease (COPD), bronchitis, bronchial hyperreactivity, asthma, cough andrhinitis; urological disorders such as urinary incontinence,pollakiuria, neurogenic or unstable bladder, cystospasm and chroniccystitis; gastrointestinal disorders such as irritable bowel syndrome,spastic colitis, diverticulitis and peptic ulceration; andcardiovascular disorders such as vagally induced sinus bradycardia. Forexample, the compounds of the present invention are useful for thetreatment of respiratory diseases such as chronic obstructive pulmonarydisease, chronic bronchitis, asthma, and rhinitis; urinary diseases suchas urinary incontinence and pollakinuria in neuripenia pollakinuria,neurogenic bladder, nocturnal enuresis, unstable bladder, cytospasm andchronic cystitis; and gastrointestinal diseases such as irritable bowelsyndrome, spastic colitis and diverticulitis.

The present invention further provides a compound of formula (I) or apharmaceutically acceptable composition comprising a compound of formula(I) for use in a method of treatment of the human or animal body bytherapy, in particular for the treatment of respiratory, urological orgastrointestinal disease or disorder.

The present invention further provides the use of a compound of formula(I) or a pharmaceutically acceptable composition comprising a compoundof formula (I) for the manufacture of a medicament for the treatment ofa respiratory, urological or gastrointestinal disease or disorder.

Further, the compounds of formula (I) and pharmaceutical compositionscomprising a compound of formula (I) can be used in a method of treatinga respiratory, urological or gastrointestinal disease or disorder, whichmethod comprises administering to a human or animal patient in need ofsuch treatment an effective, non-toxic, amount of a compound of formula(I) or a pharmaceutical composition comprising a compound of formula(I).

Further, the compounds of formula (I) and pharmaceutical compositionscomprising a compound of formula (I) can be used in combination withother drugs effective in the treatment of these diseases. For examplewith β₂ agonists, steroids, antiallergic drugs, phosphodiesterase IVinhibitors and/or leukotriene D4 (LTD4) inhibitors, for simultaneous,separate or sequential use in the treatment of a respiratory disease.

The present invention therefore further provides a combination productcomprising

-   -   (i) a compound according to the invention; and    -   (ii) another compound effective in the treatment of a        respiratory, urological or gastrointestinal disease or disorder

for simultaneous, separate or sequential use.

The compound (ii) which is effective in the treatment of a respiratory,urological or gastrointestinal disease or disorder may be a β₂ agonist,steroid, antiallergic drug, phosphodiesterase IV inhibitor and/orleukotriene D4 (LTD4) antagonist when the product is for simultaneous,separate or sequential use in the treatment of a respiratory disease.Alternatively, the compound (ii) may be a β₂ agonist, steroid,antiallergic drug and/or phosphodiesterase IV inhibitor when the productis for simultaneous, separate or sequential use in the treatment of arespiratory disease.

The present invention will be further illustrated by the followingexamples. The examples are given by way of illustration only and are notto be construed as limiting.

Example 1(3R)-3-(2,3-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as a mixture of diastereomersaccording to methods c, and b from the Intermediate I-2. The yield ofthe final step was 20 mg, 71%.

MS [M-CF₃COO]⁺: 470.

¹H-NMR (DMSO-d₆): δ 1.50-1.72 (m, 2H), 1.75-1.95 (m, 2H), 1.97-2.15 (m,3H), 2.95-3.15 (m, 4H), 3.20-3.50 (m, 5H), 3.75-3.85 (m, 1H), 3.95-4.15(m, 3H), 4.95-5.05 (m, 1H), 6.90-7.0 (m, 4H), 7.15-7.45 (m, 11H).

Example 2(3R)-3-(2,3-Diphenylpropionyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as a mixture of diastereomersaccording to methods c, and b from the Intermediate I-2. The yield ofthe final step was 15 mg, 55%.

MS [M-CF₃COO]⁺: 460.

¹H-NMR (DMSO-d₆): δ 1.50-1.70 (m, 2H), 1.70-2.0 (m, 4H), 2.0-2.15 (m,1H), 2.75-2.85 (m, 2H), 2.85-3.20 (m, 4H), 3.20-3.45 (m, 5H), 3.70-3.82(m, 1H), 4.02-4.12 (m, 1H), 4.95-5.02 (m, 1H), 6.90-7.05 (m, 2H),7.10-7.45 (m, 11H)

Example 3(3R)-3-[(2*)-2-Hydroxymethyl-2,3-diphenylpropionyloxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (Diastereomer 1)

The title compound was synthesised according to methods e, and b fromthe Intermediate I-22a. The yield of the final step was 15 mg, 52%.

MS [M-CF₃COO]⁺: 490.

¹H-NMR (DMSO-d₆): δ 1.55-1.75 (m, 2H), 1.75-2.05 (m, 4H), 2.21 (m, 1H),2.75-2.85 (m, 2H), 2.85-2.95 (m, 1H), 3.05-3.45 (m, 8H), 3.75-3.87 (m,2H), 3.92-4.0 (m, 1H), 5.08 (m, 1H), 5.20-5.23 (t, 1H, OH), 6.82-6.90(m, 2H), 6.90-6.95 (m, 1H), 6.95-7.02 (m, 1H), 7.05-7.20 (m, 5H),7.20-7.35 (m, 3H), 7.37-7.42 (m, 1H).

Example 4(3R)-3-[(2*)-2-Hydroxymethyl-2,3-diphenylpropionyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (Diastereomer 1)

The title compound was synthesised according to methods e, and b fromthe Intermediate I-22a. The yield of the final step was 18 mg, 64%.

MS [M-CF₃COO]⁺: 470.

¹H-NMR (DMSO-d₆): δ 1.62-1.75 (m, 2H), 1.80-2.05 (m, 2H), 2.26 (m, 1H),2.90-3.12 (m, 3H), 3.20-3.55 (m, 8H), 3.80-4.02 (m, 3H), 5.10-5.17 (m,1H), 5.20-5.25 (t, 1H, OH), 6.82-6.90 (m, 2H), 7.10-7.20 (m, 5H),7.22-7.40 (m, 8H).

Example 5(3R)-3-[(2*)-2-Hydroxymethyl-2,3-diphenylproponyloxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (Diastereomer 2)

The title compound was synthesised according to methods e, and b fromthe Intermediate I-22b. The yield of the final step was 10.1 mg, 37.5%.

MS [M-CF₃COO]⁺: 490.

¹H-NMR (DMSO-d₆): δ 1.45-1.60 (m, 1H), 1.60-1.75 (m, 1H), 1.80-2.05 (m,4H), 2.18 (m, 1H), 2.75-2.90 (m, 2H), 2.95-3.10 (m, 1H), 3.10-3.55 (m,8H), 3.75-3.92 (m, 2H), 4.0-4.12 (m, 1H), 5.05-5.15 (m, 1H), 5.25-5.35(t, 1H, OH), 6.70-6.85 (m, 2H), 6.90-7.20 (m, 7H), 7.20-7.35 (m, 3H),7.35-7.42 (m, 1H).

Example 6(3R)-3-[(2*)-2-Hydroxymethyl-2,3-diphenylpropionyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (Diastereomer 2)

The title compound was synthesised according to methods e, and b fromthe Intermediate I-22b. The yield of the final step was 22 mg, 76%.

MS [M-CF₃COO]⁺: 470.

¹H-NMR (DMSO-d₆): δ 1.50-1.60 (m, 1H), 1.60-1.80 (m, 1H), 1.85-2.05 (m,2H), 2.21 (m, 1H), 2.90-3.10 (m, 2H), 3.12-3.55 (m, 9H), 3.78-3.83 (m,1H), 3.88-3.95 (m, 1H), 4.07-4.12 (m, 1H), 5.15-5.20 (m, 1H), 5.35-5.40(t, 1H, OH), 6.75-6.80 (m, 2H), 7.0-7.15 (m, 3H), 7.20-7.40 (m, 8H).

Example 7(3R)-3-[(2*)-2-Hydroxy-2,3-diphenylpropionyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide (Diastereomer 1)

The title compound was synthesised according to methods d, and a fromthe Intermediate I-17a. The yield of the final step was 380 mg, 96%.

MS [M-Br]⁺: 486, mp: 103° C.

¹H-NMR (DMSO-d₆): δ 1.65-1.75 (m, 2H), 1.75-2.02 (m, 2H), 2.02-2.15 (m,2H), 2.24 (m, 1H), 3.05-3.25 (m, 2H), 3.25-3.55 (m, 7H), 3.78-3.90 (m,1H), 3.98-4.08 (m, 2H), 5.02-5.10 (m, 1H), 6.20 (s, 1H, OH), 6.92-7.0(m, 3H), 7.10-7.22 (m, 5H), 7.25-7.40 (m, 5H), 7.52-7.58 (m, 2H).

Example 8(3R)-3-[(2*)-2-Hydroxy-2,3-diphenylpropionyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide (Diastereomer 1)

The title compound was synthesised according to methods d, and a fromthe Intermediate I-17a. The yield of the final step was 320 mg, 83%.

MS [M-Br]⁺: 472, mp: 223° C.

¹H-NMR (DMSO-d₆): δ 1.70-1.80 (m, 2H), 1.80-2.0 (m, 2H), 2.20 (m, 1H),3.15-3.55 (m, 7H), 3.55-3.70 (m, 2H), 3.85-4.0 (m, 1H), 4.30-4.45 (m,2H), 5.0-5.10 (m, 1H), 6.10 (s, 1H, OH), 6.90-7.05 (m, 3H), 7.05-7.20(m, 5H), 7.20-7.40 (m, 5H), 7.45-7.55 (m, 2H).

Example 9(3R)-3-[(2*)-2-Hydroxy-2,3-diphenylpropionyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (Diastereomer 2)

The title compound was synthesised according to methods d, and b fromthe Intermediate I-17b. The yield of the final step was 7.2 mg, 25%.

MS [M-CF₃COO]⁺: 486.

¹H-NMR (DMSO-d₆): δ 1.40-1.55 (m, 1H), 1.55-1.70 (m, 1H), 1.75-2.0 (m,2H), 2.11 (m, 3H), 3.10-3.60 (m, 9H), 3.77-3.87 (m, 1H), 4.0-4.1 (m,2H), 5.0-5.1 (m, 1H), 6.14 (s, 1H, OH), 6.90-7.0 (m, 3H), 7.15-7.25 (m,5H), 7.25-7.42 (m, 5H), 7.60-7.67 (m, 2H).

Example 10(3R)-3-[(2*)-2-Hydroxy-2,3-diphenylpropionyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (Diastereomer 2)

The title compound was synthesised according to methods d, and b fromthe Intermediate I-17b. The yield of the final step was 5.4 mg, 19%.

MS [M-CF₃COO]⁺: 472.

¹H-NMR (DMSO-d₆): δ 1.40-1.55 (m, 1H), 1.55-1.70 (m, 1H), 1.80-2.0 (m,2H), 2.12 (m, 1H), 3.20-3.60 (m, 7H), 3.60-3.70 (m, 2H), 3.90-4.0 (m,1H), 4.42 (m, 2H), 5.0-5.1 (m, 1H), 6.15 (s, 1H, OH), 6.95-7.05 (m, 3H),7.10-7.22 (m, 5H), 7.25-7.40 (m, 5H), 7.57-7.65 (m, 2H).

Example 11(3R)-3-(2-Hydroxy-3-phenyl-2-thien-2-ylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as a mixture of diastereomersaccording to methods d, and b from Intermediate I-18. The yield of thefinal step was 15 mg, 52%.

MS [M-CF₃COO]⁺: 492.

¹H-NMR (DMSO-d₆): δ 1.45-1.70 (m, 1H), 1.75-2.0 (m, 3H), 2.0-2.30 (m,3H), 3.0-3.17 (m, 1H), 3.17-3.57 (m, 8H), 3.80-3.90 (m, 1H), 3.97-4.10(m, 2H), 5.02-5.05 (m, 1H), 6.52-6.60 (d, 1H, OH), 6.90-7.04 (m, 4H),7.14-7.28 (m, 6H), 7.28-7.38 (m, 2H), 7.42-7.50 (m, 1H).

Example 12(3R)-3-(2-Hydroxy-3-phenyl-2-thien-2-ylpropionyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as a mixture of diastereomersaccording to methods d, and b from Intermediate I-18. The yield of thefinal step was 21 mg, 74%.

MS [M-CF₃COO]⁺: 482

¹H-NMR (DMSO-d₆): δ 1.45-1.70 (m, 1H), 1.75-2.05 (m, 5H), 2.05-2.3 (m,1H), 2.77-2.87 (m, 2H), 2.90-3.10 (m, 1H), 3.10-3.52 (m, 8H), 3.75-3.82(m, 1H), 5.0-5.07 (m, 1H), 6.52-6.57 (d, 1H, OH), 6.92-7.05 (m, 3H),7.10-7.27 (m, 6H), 7.37-7.47 (m, 2H).

Example 13(3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide

The title compound was obtained as a mixture of diastereomers accordingto methods c, and a from Intermediate I-3. The yield of the final stepwas 300 mg, 71%.

MS [M-Br]⁺: 442, mp: 157°, (described in experimental section, method a)

¹H-NMR (DMSO-d₆): δ 1.70-2.05 (m, 4H), 2.05-2.35 (m, 3H), 2.70-2.83 (m,1H), 2.90-3.02 (m, 1H), 3.25-3.60 (m, 7H), 3.82-3.97 (m, 1H), 3.97-4.10(m, 2H), 5.05-5.25 (m, 3H), 5.70-5.90 (m, 1H), 6.50 (d, 1H, OH),6.90-7.05 (m, 4H), 7.10-7.20 (m, 1H), 7.27-7.35 (m, 2H), 7.45 (m, 1H).

Example 14(3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was obtained as a mixture of diastereomers accordingto methods c, and b from Intermediate I-3. The yield of the final stepwas 10 mg, 39.3%.

MS [M-CF₃COO]⁺: 432.

¹H-NMR (DMSO-d₆): δ 1.65-2.18 (m, 6H), 2.18-2.30 (m, 1H), 2.70-3.05 (m,4H), 3.10-3.55 (m, 4H), 3.55-3.68 (m, 1H), 3.78-3.92 (m, 2H), 4.0-4.1(m, 1H), 5.0-5.20 (m, 3H), 5.70-5.85 (m, 1H), 6.48-6.52 (d, 1H, OH),6.90-7.02 (m, 3H), 7.10-7.20 (m, 1H), 7.35-7.42 (m, 1H), 7.42-7.50 (m,1H).

Example 15(3R)-3-(2-Hydroxy-2-thien-2-ylpent-4-enoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide

The title compound was obtained as a mixture of diastereomers accordingto methods c, and a from Intermediate I-3. The yield of the final stepwas 270 mg, 66%.

MS [M-Br]⁺: 428, mp: 82° C.

¹H-NMR (DMSO-d₆): δ 1.72-2.10 (m, 4H), 2.20-2.35 (m, 1H), 2.70-2.85 (m,1H), 2.90-3.05 (m, 1H), 3.25-3.85 (m, 7H), 3.92-4.12 (m, 1H), 4.35-4.45(m, 2H), 4.95-5.20 (m, 3H), 5.70-5.90 (m, 1H), 6.50 (s, 1H, OH),6.90-7.05 (m, 4H), 7.10-7.18 (m, 1H), 7.25-7.45 (m, 3H).

Example 16(3R)-3-(2-Hydroxy-2-thien-2-ylheptanoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was obtained as a mixture of diastereomers accordingto methods c, and b from Intermediate I-1. The yield of the final stepwas 16.2 mg, 57%.

MS [M-CF₃COO]⁺: 472.

¹H-NMR (DMSO-d₆): δ 0.80-0.90 (m, 3H), 1.15-1.40 (m, 6H), 1.65-2.30 (m,9H), 3.20-3.60 (m, 5H), 3.85-3.95 (m, 1H), 3.95-4.10 (m, 2H), 5.05-5.17(m, 1H), 6.30-6.35 (d, 1H, OH), 6.90-7.05 (m, 4H), 7.10-7.17 (m, 1H),7.25-7.35 (m, 2H), 7.42-7.48 (m, 1H).

Example 17(3R)-3-(2-Hydroxy-2-thien-2-ylheptanoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was obtained as a mixture of diastereomers accordingto methods c, and b from Intermediate I-1. The yield of the final stepwas 6.8 mg, 12%.

MS [M-CF₃COO]⁺: 462.

¹H-NMR (DMSO-d₆): δ 0.80-0.90 (m, 3H), 1.15-1.40 (m, 6H), 1.65-2.30 (m,9H), 2.80-2.85 (m, 2H), 3.10-3.55 (m, 7H), 3.75-3.90 (m, 1H), 5.10 (m,1H), 6.30-6.32 (d, 1H, OH), 6.90-6.95 (m, 1H), 6.95-7.02 (m, 2H),7.09-7.13 (m, 1H), 7.37-7.39 (m, 1H), 7.40-7.45 (m, 1H).

Example 18(3R)-3-(2-Hydroxy-2-thien-2-ylpent-3-ynoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was obtained as a mixture of diastereomers accordingto methods d, and b from Intermediate I-19. The yield of the final stepwas 6.4 mg, 12%.

MS [M-CF₃COO]⁺: 440.

¹H-NMR (DMSO-d₆): δ 1.60-2.05 (m, 7H), 2.05-2.20 (m, 2H), 2.20-2.35 (m,1H), 3.10-3.60 (m, 7H), 3.82-3.97 (m, 1H), 3.97-4.10 (m, 2H), 5.13 (m,1H), 6.90-7.06 (m, 4H), 7.20-7.38 (m, 4H), 7.50-7.56 (m, 1H).

Example 19(3R)-3-(2-Hydroxy-2-thien-2-ylpent-3-ynoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was obtained as a mixture of diastereomers accordingto methods d, and b from Intermediate I-19. The yield of the final stepwas 2.4 mg, 4.3%.

MS [M-CF₃COO]⁺: 430

¹H-NMR (DMSO-d₆): δ 1.60-2.10 (m, 9H), 2.20-2.35 (m, 1H), 2.75-2.90 (m,2H), 3.10-3.70 (m, 7H), 3.75-3.95 (m, 1H), 5.12 (m, 1H), 6.91-7.04 (m,3H), 7.19-7.42 (m, 3H), 7.48-7.55 (m, 1H).

Example 20(3R)-3-(2-Hydroxy-2-thien-2-ylbut-3-enoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was obtained as a mixture of diastereomers accordingto methods d, and b from Intermediate I-20. The yield of the final stepwas 9.6 mg, 16%.

MS [M-CF₃COO]⁺: 428

¹H-NMR (DMSO-d₆): δ 1.60-2.05 (m, 4H), 2.05-2.20 (m, 2H), 2.20-2.38 (m,1H), 3.15-3.60 (m, 7H), 3.82-3.95 (m, 1H), 3.98-4.10 (m, 2H), 5.10-5.20(m, 1H), 5.25-5.35 (m, 1H), 5.45-5.55 (m, 1H), 6.45-6.55 (m, 1H),6.75-6.82 (d, 1H, OH), 6.92-6.96 (m, 3H), 6.98-7.03 (m, 1H), 7.13-7.15(m, 1H), 7.28-7.34 (m, 1H), 7.48-7.52 (m, 1H).

Example 21(3R)-3-(2-Hydroxy-2-thien-2-ylbut-3-enoyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was obtained as a mixture of diastereomers accordingto methods d, and b from Intermediate I-20. The yield of the final stepwas 5.8 mg, 10%.

MS [M-CF₃COO]⁺: 418

¹H-NMR (DMSO-d₆): δ 1.60-2.20 (m, 6H), 2.20-2.35 (m, 1H), 2.79-2.84 (m,2H), 3.10-3.55 (m, 7H), 3.80-3.90 (m, 1H), 5.10-5.20 (m, 1H), 5.25-5.35(m, 1H), 5.45-5.55 (m, 1H), 6.45-6.55 (m, 1H), 6.75-6.78 (d, 1H, OH),6.92-6.95 (m, 1H), 6.95-7.05 (m, 2H), 7.10-7.15 (m, 1H), 7.35-7.42 (m,1H), 7.45-7.52 (m, 1H).

Example 22(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide

The title compound was synthesised according to methods d, and a fromthe Intermediate I-15a. The yield of the final step was 230 mg, 85%.

MS [M-Br]⁺: 470, mp: 171° C.

¹H-NMR (DMSO-d₆): δ 1.27-1.67 (m, 8H), 1.8-2.05 (m, 4H), 2.05-2.20 (m,2H), 2.25-2.35 (m, 1H), 2.70-2.92 (m, 1H), 3.20-3.25 (m, 1H), 3.25-3.60(m, 6H), 3.80-3.95 (m, 1H), 3.95-4.08 (m, 2H), 5.10-5.20 (m, 1H), 6.18(s, 1H, OH), 6.87-7.05 (m, 4H), 7.08-7.20 (m, 1H), 7.25-7.37 (m, 2H),7.40-7.47 (m, 1H).

Example 23(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-yl-acetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised according to methods d, and b fromthe Intermediate I-15a. The yield of the final step was 21 mg, 75%.

MS [M-CF₃COO]⁺: 460

¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.80-2.10 (m, 6H), 2.28 (m, 1H),2.75-2.85 (m, 3H), 3.10-3.55 (m, 7H), 3.80-3.90 (m, 1H), 5.05-5.15 (m,1H), 6.20 (s, 1H, OH), 6.90-6.95 (m, 1H), 6.95-7.05 (m, 2H), 7.10-7.20(m, 1H), 7.35-7.45 (m, 2H).

Example 24(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide

The title compound was synthesised according to methods c, and a fromthe Intermediate I-15a. The yield of the final step was 338 mg, 92%.

MS [M-Br]⁺: 456; mp: 75° C.

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.10 (m, 4H), 2.27-2.35 (m,1H), 2.70-2.90 (m, 1H), 3.30-3.68 (m, 5H), 3.68-3.83 (m, 2H), 3.92-4.10(m, 1H), 4.32-4.50 (m, 2H), 5.10-5.20 (m, 1H), 6.20 (s, 1H, OH),6.90-7.05 (m, 4H), 7.10-7.20 (m, 1H), 7.30-7.42 (m, 3H).

Example 25(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 17 mg, 64%.

MS [M-CF₃COO]⁺: 440

¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.80-2.10 (m 4H), 2.32 (m, 1H),2.75-2.85 (m, 1H), 2.95-3.05 (m, 2H), 3.20-3.50 (m, 6H), 3.50-3.65 (m,1H), 3.85-3.95 (m, 1H), 5.10-5.20 (m, 1H), 6.22 (s, 1H, OH), 6.95-7.05(m, 1H), 7.10-7.20 (m, 1H), 7.20-7.40 (m, 5H), 7.40-7.55 (m, 1H)

Example 26(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 20 mg, 74%.

MS [M-CF₃COO]⁺: 454

¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.75-2.05 (m, 6H), 2.28 (m, 1H),2.55-2.65 (m, 2H), 2.75-2.85 (m, 1H), 3.10-3.40 (m, 6H), 3.40-3.55 (m,1H), 3.77-3.87 (m, 1H), 5.05-5.15 (m, 1H), 6.20 (s, 1H, OH), 6.95-7.0(m, 1H), 7.10-7.15 (m, 1H), 7.20-7.35 (m, 5H), 7.38-7.42 (m, 1H).

Example 27(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 3 mg, 12%.

MS [M-CF₃COO]⁺: 452

¹H-NMR (DMSO-d₆): δ 1.25-1.60 (m, 8H), 1.80-2.10 (m, 4H), 2.31 (m, 1H),2.72-2.85 (m, 1H), 3.12-3.22 (m, 1H), 3.22-3.45 (m, 3H), 3.45-3.60 (m,1H), 3.82-3.92 (m, 1H), 3.95-4.10 (m, 2H), 5.10-5.20 (m, 1H), 6.20 (s,1H, OH), 6.35-6.50 (m, 1H), 6.82-6.95 (m, 2H), 7.10-7.15 (m, 1H),7.25-7.47 (m, 4H), 7.55-7.62 (m, 2H).

Example 28(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 15 mg, 52%.

MS [M-CF₃COO]⁺: 488

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.80-2.05 (m, 4H), 2.05-2.17 (m,2H), 2.30 (m, 1H), 2.75-2.90 (m, 1H), 3.17-3.27 (m, 1H), 3.27-3.60 (m,6H), 3.82-3.95 (m, 1H), 3.97-4.05 (m, 2H), 5.14 (m, 1H), 6.22 (s, 1H,OH), 6.92-7.05 (m, 3H), 7.10-7.20 (m, 3H), 7.40-7.55 (m, 1H).

Example 29(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(4-oxo-4-thien-2-ylbutyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 4 mg, 14%.

MS [M-CF₃COO]⁺: 488

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.70-2.05 (m, 6H), 2.30 (m, 1H),2.75-2.90 (m, 1H), 3.05-3.12 (m, 2H), 3.15-3.60 (m, 7H), 3.80-3.92 (m,1H), 5.13 (m, 1H), 6.22 (s, 1H, OH), 6.98-7.02 (m, 1H), 7.12-7.18 (m,1H), 7.25-7.30 (m, 1H), 7.40-7.55 (m, 1H), 7.95-8.0 (m, 1H), 8.02-8.07(m, 1H).

Example 30(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[4-(4-fluorophenyl)-4-oxobutyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 9 mg, 29%.

MS [M-CF₃COO]⁺: 500

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.05 (m, 6H), 2.30 (m, 1H),2.75-2.90 (m, 1H), 3.05-3.60 (m, 9H), 3.80-3.95 (m, 1H), 5.14 (m, 1H),6.22 (s, 1H, OH), 6.98-7.02 (m, 1H), 7.12-7.20 (m, 1H), 7.35-7.45 (m,3H), 8.02-8.12 (m, 2H).

Example 31(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(3-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 14 mg, 48%.

MS [M-CF₃COO]⁺: 486

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.80-2.0 (m, 4H), 2.0-2.20 (m,2H), 2.30 (m, 1H), 2.75-2.90 (m, 1H), 3.17-3.25 (m, 1H), 3.25-3.60 (m,6H), 3.82-3.92 (m, 1H), 3.94-4.02 (m, 2H), 5.14 (m, 1H), 6.21 (s, 1H,OH), 6.30-6.42 (m, 3H), 6.95-7.10 (m, 2H), 7.12-7.20 (m, 1H), 7.20-7.45(m, 1H), 9.47 (s, 1H, OH).

Example 321-(2-Benzyloxyethyl)-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 10 mg, 35%.

MS [M-CF₃COO]⁺: 470

¹H-NMR (DMSO-d₆): δ 1.25-1.62 (m, 8H), 1.80-2.07 (m, 4H), 2.30 (m, 1H),2.75-2.85 (m, 1H), 3.0-3.65 (m, 7H), 3.75-4.0 (m, 3H), 4.50 (s, 2H),5.10-5.17 (m, 1H), 6.21 (s, 1H, OH), 6.95-7.0 (m, 1H), 7.10-7.17 (m,1H), 7.27-7.45 (m, 6H).

Example 33(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-o-tolyloxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 13 mg, 45%.

MS [M-CF₃COO]⁺: 484

¹H-NMR (DMSO-d₆): δ 1.23-1.65 (m, 8H), 1.80-2.05 (m, 4H), 2.05-2.20 (m,5H), 2.31 (m, 1H), 2.75-2.90 (m, 1H), 3.15-3.25 (m, 1H), 3.27-3.60 (m,6H), 3.85-3.95 (m, 1H), 3.97-4.05 (m, 2H), 5.15 (m, 1H), 6.22 (s, 1H,OH), 6.83-6.93 (m, 2H), 6.98-7.02 (m, 1H), 7.12-7.20 (m, 3H), 7.40-7.46(m, 1H).

Example 341-[3-(3-Cyanophenoxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 11 mg, 32%.

MS [M-CF₃COO]⁺: 495

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.05 (m, 4H), 2.05-2.20 (m,2H), 2.30 (m, 1H), 2.75-2.90 (m, 1H), 3.20-3.25 (m, 1H), 3.25-3.60 (m,6H), 3.82-3.95 (m, 1H), 4.05-4.15 (m, 2H), 5.07-5.20 (m, 1H), 6.20 (s,1H, OH), 6.95-7.05 (m, 1H), 7.12-7.20 (m, 1H), 7.25-7.35 (m, 1H),7.40-7.57 (m, 4H)

Example 35(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(naphthalen-1-yloxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 10 mg, 26%.

MS [M-CF₃COO]⁺: 520, (described in experimental section, method b).

¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.80-2.10 (m, 4H), 2.20-2.37 (m,3H), 2.75-2.92 (m, 1H), 3.20-3.65 (m, 7H), 3.90-4.05 (m, 1H), 4.15-4.30(m, 2H), 5.15-5.22 (m, 1H), 6.24 (s, 1H, OH), 6.95-7.05 (m, 2H),7.15-7.20 (m, 1H), 7.40-7.60 (m, 5H), 7.85-7.95 (m, 1H), 8.20-8.25 (m,1H)

Example 36(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(methylphenylamino)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 12 mg, 35%.

MS [M-CF₃COO]⁺: 483

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.02 (m, 6H), 2.28 (m, 1H),2.75-2.85 (m, 1H), 2.87 (s, 3H), 3.09-3.14 (m, 1H), 3.15-3.55 (m, 8H),3.75-3.87 (m, 1H), 5.05-5.15 (m, 1H), 6.20 (s, 1H, OH), 6.60-6.70 (m,1H), 6.70-6.77 (m, 2H), 6.92-7.0 (m, 1H), 7.10-7.25 (m, 3H), 7.35-7.45(m, 1H).

Example 37(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 7 mg, 22%.

MS [M-CF₃COO]⁺: 486

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.02 (m, 6H), 2.27 (m, 1H),2.75-2.90 (m, 1H), 2.95-3.05 (m, 2H), 3.07-3.15 (m, 1H), 3.15-3.52 (m,6H), 3.75-3.87 (m, 1H), 5.05-5.15 (m, 1H), 6.20 (s, 1H, OH), 6.95-7.0(m, 1H), 7.12-7.17 (m, 1H), 7.20-7.30 (m, 1H), 7.30-7.45 (m, 5H).

Example 38(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 9 mg, 26%.

MS [M-CF₃COO]⁺: 482

¹H-NMR (DMSO-d₆): δ 1.30-1.67 (m, 8H), 1.72-2.10 (m, 6H), 2.30 (m, 1H),2.75-2.90 (m, 1H), 3.10-3.60 (m, 9H), 3.85-3.95 (m, 1H), 5.10-5.20 (m,1H), 6.23 (s, 1H, OH), 6.95-7.05 (m, 1H), 7.12-7.20 (m, 1H), 7.40-7.47(m, 1H), 7.52-7.60 (m, 2H), 7.62-7.72 (m, 1H), 7.95-8.05 (m, 1H).

Example 39(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(2,4,6-trimethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 13 mg, 35%.

MS [M-CF₃COO]⁺: 512

¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.80-2.02 (m, 4H), 2.02-2.25 (m,11H), 2.32 (m, 1H), 2.75-2.90 (m, 1H), 3.23-3.28 (m, 1H), 3.28-3.62 (m,6H), 3.65-3.80 (m, 2H), 3.85-3.97 (m, 1H), 5.10-5.20 (m, 1H), 6.22 (s,1H, OH), 6.82 (s, 2H), 6.97-7.05 (m, 1H), 7.12-7.20 (m, 1H), 7.40-7.47(m, 1H)

Example 401-[3-(2-Chlorophenoxy)-propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 13 mg, 36%.

MS [M-CF₃COO]⁺: 505

¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.75-2.05 (m, 4H), 2.05-2.25 (m,2H), 2.31 (m, 1H), 2.75-2.90 (m, 1H), 3.19-3.23 (m, 1H), 3.23-3.62 (m,6H), 3.85-4.0 (m, 1H), 4.07-4.15 (m, 2H), 5.10-5.20 (m, 1H), 6.22 (s,1H, OH), 6.92-7.05 (m, 2H), 7.12-7.22 (m, 2H), 7.27-7.37 (m, 1H),7.40-7.50 (m, 2H).

Example 41(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(3-trifluoromethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 13 mg, 33%.

MS [M-CF₃COO]⁺: 538

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.05 (m, 4H), 2.05-2.25 (m,2H), 2.31 (m, 1H), 2.75-2.90 (m, 1H), 3.20-3.25 (m, 1H), 3.25-3.62 (m,6H), 3.82-3.97 (m, 1H), 4.05-4.20 (m, 2H), 5.10-5.20 (m, 1H), 6.22 (s,1H, OH), 6.95-7.05 (m, 1H), 7.12-7.20 (m, 1H), 7.22-7.30 (m, 2H),7.30-7.37 (m, 1H), 7.40-7.47 (m, 1H), 7.50-7.62 (m, 1H).

Example 421-[3-(Biphenyl-4-yloxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 11 mg, 30%.

MS [M-CF₃COO]⁺: 546

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.77-2.05 (m, 4H), 2.05-2.25 (m,2H), 2.31 (m, 1H), 2.75-2.92 (m, 1H), 3.20-3.23 (m, 1H), 3.23-3.62 (m,6H), 3.85-3.97 (m, 1H), 4.05-4.15 (m, 2H), 5.10-5.20 (m, 1H), 6.22 (s,1H, OH), 6.95-7.10 (m, 3H), 7.12-7.20 (m, 1H), 7.27-7.37 (m, 1H),7.40-7.50 (m, 3H), 7.55-7.70 (m, 4H).

Example 43(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(2,4-difluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 10 mg, 28%.

MS [M-CF₃COO]⁺: 506

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.05 (m, 4H), 2.05-2.15 (m,2H), 2.30 (m, 1H), 2.82 (m, 1H), 3.17-3.28 (m, 1H), 3.28-3.47 (m, 5H),3.47-3.60 (m, 1H), 3.82-3.95 (m, 1H), 4.05-4.15 (m, 2H), 5.14 (m, 1H),6.22 (s, 1H, OH), 6.95-7.10 (m, 2H), 7.12-7.38 (m, 3H), 7.40-7.45 (m,1H).

Example 44(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-methoxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 11 mg, 32%.

MS [M-CF₃COO]⁺: 500

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.15 (m, 6H), 2.30 (m, 1H),2.82 (m, 1H), 3.18-3.25 (m, 1H), 3.25-3.45 (m, 5H), 3.45-3.60 (m, 1H),3.70 (s, 3H), 3.82-3.92 (m, 1H), 3.92-4.02 (m, 2H), 5.14 (m, 1H), 6.22(s, 1H, OH), 6.88 (m, 4H), 6.98-7.02 (m, 1H), 7.15-7.16 (m, 1H),7.42-7.44 (m, 1H).

Example 45(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 14 mg, 38%.

MS [M-CF₃COO]⁺: 524

¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.65-1.75 (m, 4H), 1.75-2.20 (m,6H) 2.30 (m, 1H), 2.50-2.70 (m, 4H), 2.75-2.95 (m, 1H), 3.17-3.25 (m,1H), 3.25-3.45 (m, 5H), 3.45-3.60 (m, 1H), 3.80-3.92 (m, 1H), 3.92-4.02(m, 2H), 5.14 (m, 1H), 6.22 (s, 1H, OH), 6.60-6.70 (m, 2H), 6.95-7.02(m, 2H), 7.15-7.20 (m, 1H), 7.42-7.45 (m, 1H).

Example 461-[3-(Benzo[1,3]dioxol-5-yloxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 13 mg, 38%.

MS [M-CF₃COO]⁺: 514

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.75-2.15 (m, 6H), 2.30 (m, 1H),2.75-2.90 (m, 1H), 3.15-3.25 (m, 1H), 3.25-3.42 (m, 5H), 3.42-3.60 (m,1H), 3.82-3.92 (m, 1H), 3.92-4.0 (m, 2H), 5.13 (m, 1H), 5.97 (s, 2H),6.20 (s, 1H, OH), 6.36-6.40 (m, 1H), 6.64-6.65 (m, 1H), 6.81-6.84 (m,1H), 6.98-7.02 (m, 1H), 7.15-7.17 (m, 1H), 7.42-7.44 (m, 1H).

Example 471-[3-(2-Carbamoyl-phenoxy)-propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-yl-acetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 13 mg, 36%.

MS [M-CF₃COO]⁺: 513

¹H-NMR (DMSO-d₆): δ 1.27.1.65 (m, 8H), 1.80-2.07 (m, 4H), 2.12-2.27 (m,2H), 2.31 (m, 1H), 2.82 (m, 1H), 3.17-3.25 (m, 1H), 3.25-3.45 (m, 5H),3.45-3.60 (m, 1H), 3.82-3.92 (m, 1H), 4.10-4.17 (m, 2H), 5.15 (m, 1H),6.23 (s, 1H, OH), 6.98-7.16 (m, 4H), 7.42-7.50 (m, 2H), 7.50-7.55 (bs,2H), 7.68-7.72 (m, 1H).

Example 48(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(3-dimethylaminophenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 14 mg, 40%.

MS [M-CF₃COO]⁺: 513

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.70-2.20 (m, 6H), 2.30 (m, 1H),2.75-2.95 (m, 7H), 3.15-3.65 (m, 7H), 3.80-4.05 (m, 3H), 5.14 (m, 1H),6.15-6.30 (m, 3H), 6.32-6.36 (m, 1H), 6.95-7.22 (m, 3H), 7.40-7.45 (m,1H).

Example 491-[3-(4-Acetylaminophenoxy)propyl]-(3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 12 mg, 34%.

MS [M-CF₃COO]⁺: 527

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m. 8H), 1.75-2.20 (m, 9H), 2.30 (m, 1H),2.82 (m, 1H), 3.17-3.28 (m, 1H), 3.28-3.45 (m, 5H), 3.45-3.60 (m, 1H),3.84-3.92 (m, 1H), 3.96-4.02 (m, 2H), 5.13 (m, 1H), 6.22 (s, 1H, OH),6.86-6.90 (m, 2H), 6.98-7.02 (m, 1H), 7.15-7.17 (m, 1H), 7.42-7.44 (m,1H), 7.48-7.52 (m, 2H), 9.85 (s, 1H, NH(CO)).

Example 50(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-methoxycarbonylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 14 mg, 37%.

MS [M-CF₃COO]⁺: 528

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.80-2.05 (m, 4H), 2.05-2.25 (m,2H), 2.31 (m, 1H), 2.82 (m, 1H), 3.17-3.28 (m, 1H), 3.28-3.45 (m, 5H),3.45-3.60 (m, 1H), 3.82 (s, 3H), 3.82-3.95 (m, 1H), 4.10-4.15 (m, 2H),5.14 (m, 1H), 6.22 (s, 1H, OH), 6.95-7.10 (m, 3H), 7.15-7.17 (m, 1H),7.43-7.45 (m, 1H), 7.92-7.97 (m, 2H).

Example 51(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 15 mg, 41%.

MS [M-CF₃COO]⁺: 515

¹H-NMR (DMSO-d₆): δ 1.27-1.65 (m, 8H), 1.77-2.07 (m, 4H), 2.10-2.27 (m,2H), 2.31 (m, 1H), 2.82 (m, 1H), 3.17-3.28 (m, 1H), 3.28-3.45 (m, 5H),3.45-3.60 (m, 1H), 3.85-3.95 (m, 1H), 4.15-4.25 (m, 2H), 5.15 (m; 1H),6.22 (s, 1H, OH), 6.97-7.02 (m, 1H), 7.14-7.18 (m, 3H), 7.42-7.45 (m,1H), 8.22-8.27 (m, 2H).

Example 52(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-hydroxymethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 23. The yield of thefinal step was 13 mg, 36%.

MS [M-CF₃COO]⁺: 500

¹H-NMR (DMSO-d₆): δ 1.25-1.65 (m, 8H), 1.77-2.05 (m, 4H), 2.05-2.20 (m,2H), 2.30 (m, 1H), 2.82 (m, 1H), 3.17-3.60 (m, 7H), 3.82-3.95 (m, 1H),3.95-4.05 (m, 2H), 4.35-4.45 (m, 2H), 5.05-5.11 (t, 1H, OH), 5.11-5.20(m, 1H), 6.22 (s, 1H, OH), 6.86-6.95 (m, 2H), 6.95-7.05 (m, 1H),7.15-7.17 (m, 1H), 7.22-7.26 (m, 2H), 7.42-7.44 (m, 1H).

Example 53(3R)-3-[(2R)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide

The title compound was synthesised according to methods d, and a fromthe Intermediate I-15b. The yield of the final step was 1.2 g (73%).

mp: 181° C. MS: [M-Br]⁺: 470.

¹H-NMR (DMSO-d₆): δ 1.30-1.70 (m, 8H), 1.70-1.80 (m, 2H), 1.80-2.05 (m,2H), 2.05-2.30 (m, 3H), 2.80-2.95 (m, 1H), 3.25-3.62 (m, 7H), 3.87-4.0(m, 1H), 4.0-4.10 (m, 2H), 5.10-5.20 (m, 1H), 6.20 (s, 1H, OH),6.95-7.05 (m, 4H), 7.15-7.25 (m, 1H), 7.25-7.37 (m, 2H), 7.42-7.45 (m,1H).

Example 54(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised according to methods d, and b fromthe Intermediate I-15b. The yield of the final step was 15 mg (54%).

MS [M-CF₃COO]⁺: 460

¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m 8H), 1.65-1.80 (m, 2H), 1.80-2.10 (m,4H), 2.21 (m, 1H), 2.77-2.90 (m, 3H), 3.15-3.40 (m, 6H), 3.40-3.557 (m,1H), 3.80-3.92 (m, 1H), 5.05-5.18 (m, 1H), 6.20 (s, 1H, OH), 6.92-6.96(m, 1H), 6.96-7.02 (m, 2H), 7.12-7.20 (m, 1H), 7.36-7.40 (m, 1H),7.40-7.46 (m, 1H)

Example 55(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 54. The yield of thefinal step was 16 mg, 58%.

MS [M-CF₃COO]⁺: 456.

¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.75-1.85 (m, 2H), 1.85-2.05 (m,2H), 2.23 (m, 1H), 2.75-2.90 (m, 1H), 3.40-3.57 (m, 4H), 3.57-3.70 (m,1H), 3.70-3.80 (m, 2H), 3.97-4.10 (m, 1H), 4.37-4.47 (m, 2H), 5.10-5.18(m, 1H), 6.20 (s, 1H, OH), 6.92-7.05 (m, 4H), 7.10-7.18 (m, 1H),7.30-7.38 (m, 2H), 7.38-7.44 (m, 1H),

Example 56(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 54. The yield of thefinal step was 13 mg, 50%.

MS [M-CF₃COO]⁺: 440.

¹H-NMR (DMSO-d₆): δ 1.35-1.65 (m, 8H), 1.65-1.85 (m, 2H), 1.85-2.05 (m,2H), 2.25 (m, 1H), 2.85-2.92 (m, 1H), 2.95-3.10 (m, 2H), 3.30-3.50 (m,6H), 3.50-3.65 (m, 1H), 3.85-4.0 (m, 1H), 5.12-5.20 (m, 1H), 6.21 (s,1H, OH), 6.95-7.05 (m, 1H), 7.15-7.20 (m, 1H), 7.25-7.40 (m, 5H),7.40-7.47 (m, 1H).

Example 57(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 54. The yield of thefinal step was 14 mg, 53%.

MS [M-CF₃COO]⁺: 454.

¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.65-1.77 (m, 2H), 1.77-2.05 (m,4H), 2.21 (s, 1H), 2.55-2.65 (m, 2H), 2.75-2.92 (m, 1H), 3.15-3.40 (m,6H), 3.40-3.55 (m, 1H), 3.80-3.90 (m, 1H), 5.06-5.16 (m, 1H), 6.19 (s,1H, OH), 6.95-7.02 (m, 1H), 7.12-7.18 (m, 1H), 7.20-7.36 (m, 5H),7.38-7.46 (m, 1H).

Example 58(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 54. The yield of thefinal step was 7 mg, 26%.

MS [M-CF₃COO]⁺: 452.

¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.75-2.05 (m, 4H), 2.24 (m, 1H),2.75-2.90 (m, 1H), 3.25-3.45 (m, 4H), 3.45-3.55 (m, 1H), 3.72-3.95 (m,1H), 4.0-4.15 (m, 2H), 5.10-5.17 (m, 1H), 6.19 (s, 1H, OH), 6.40-6.55(m, 1H), 6.82-6.70 (m, 2H), 7.12-7.17 (m, 1H), 7.30-7.45 (m, 4H),7.55-7.62 (m, 2H)

Example 59(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 54. The yield of thefinal step was 19 mg, 64%.

MS [M-CF₃COO]⁺: 488.

¹H-NMR (DMSO-d₆): δ 1.30-1.65 (m, 8H), 1.65-1.80 (m, 2H), 1.80-2.05 (m,2H), 2.05-2.20 (m, 2H), 2.23 (m, 1H), 2.80-2.95 (m, 1H), 3.20-3.60 (m,7H), 3.85-3.95 (m, 1H), 3.97-4.07 (m, 2H), 5.14 (m, 1H), 6.20 (s, 1H,OH), 6.90-7.05 (m, 3H), 7.10-7.20 (m, 3H), 7.40-7.47 (m, 1H).

Example 60(3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised according to methods d, and b fromIntermediate I-14a. The yield of the final step was 4 mg, 15%.

MS [M-CF₃COO]⁺: 454

¹H-NMR (DMSO-d₆): δ 1.45-1.67 (m, 9H), 1.67-1.80 (m, 1H), 1.80-2.05 (m,2H), 2.05-2.22 (m, 3H), 2.85-2.95 (m, 1H), 3.20-3.55 (m, 7H), 3.85-3.95(m, 1H), 4.0-4.10 (m, 2H), 5.10-5.20 (m, 1H), 6.03 (s, 1H), 6.40-6.45(m, 2H), 6.90-7.0 (m, 3H), 7.27-7.35 (m, 2H), 7.62 (m, 1H)

Example 61(3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 60. The yield of thefinal step was 2 mg, 7%.

MS [M-CF₃COO]⁺: 444

¹H-NMR (DMSO-d₆): δ 1.40-1.66 (m, 9H), 1.66-2.10 (m, 5H), 2.17 (m, 1H),2.78-2.90 (m, 3H), 3.14-3.50 (m, 7H), 3.80-3.90 (m, 1H), 5.10-5.18 (m,1H), 6.02 (s, 1H), 6.38-6.46 (m, 2H), 6.92-7.02 (m, 2H), 7.36-7.40 (m,1H), 7.60 (m, 1H).

Example 62(3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 60. The yield of thefinal step was 4 mg, 17%.

MS [M-CF₃COO]⁺: 424

¹H-NMR (DMSO-d₆): δ 1.40-2.05 (m, 12H), 2.20 (m, 1H), 2.88 (m, 1H),2.95-3.05 (m, 2H), 3.20-3.60 (m, 7H), 3.85-3.95 (m, 1H), 5.18 (m, 1H),6.03 (s, 1H, OH), 6.40-6.45 (m, 2H), 7.25-7.40 (m, 5H), 7.62 (m, 1H).

Example 63(3R)-3-[(2S)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 60. The yield of thefinal step was 10 mg, 36.2%.

MS [M-CF₃COO]⁺: 438

¹H-NMR (DMSO-d₆): δ 1.35-2.05 (m, 14H), 2.16 (m, 1H), 2.55-2.65 (m, 2H),2.75-2.95 (m, 1H), 3.10-3.55 (m, 7H), 3.77-3.92 (m, 1H), 5.05-5.15 (m,1H), 6.02 (s, 1H, OH), 6.35-6.45 (m, 2H), 7.17-7.40 (m, 5H), 7.60 (m,1H).

Example 64(3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised according to methods d, and b fromIntermediate I-14b. The yield of the final step was 12 mg, 46%.

MS [M-CF₃COO]⁺: 454

¹H-NMR (DMSO-d₆): δ 1.40-1.60 (m, 8H), 1.75-2.05 (m, 4H), 2.05-2.20 (m,2H), 2.30 (m, 1H), 2.75-2.87 (m, 1H), 3.10-3.60 (m, 7H), 3.85-3.95 (m,1H), 3.97-4.07 (m, 2H), 5.10-5.17 (m, 1H), 6.04 (s, 1H), 6.40-6.50 (m,2H), 6.90-7.0 (m, 3H), 7.27-7.37 (m, 2H), 7.60-7.65 (m, 1H).

Example 65(3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 64. The yield of thefinal step was 14 mg, 55%.

MS [M-CF₃COO]⁺: 444

¹H-NMR (DMSO-d₆): δ 1.40-1.65 (m, 8H), 1.75-2.10 (m, 6H), 2.27 (m, 1H),2.70-2.90 (m, 3H), 3.0-3.55 (m, 7H), 3.77-3.82 (m, 1H), 5.05-5.15 (m,1H), 6.03 (s, 1H), 6.40-6.45 (m, 2H), 6.90-7.05 (m, 2H), 7.35-7.42 (m,1H), 7.55-7.65 (m, 1H).

Example 66(3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 64. The yield of thefinal step was 15 mg, 57%.

MS [M-CF₃COO]⁺: 424

¹H-NMR (DMSO-d₆): δ 1.30-2.40 (m, 13H), 2.75-2.85 (m, 1H), 2.95-3.05 (m,2H), 3.10-3.75 (m, 7H), 3.85-4.0 (m, 1H), 5.05-5.15 (m, 1H), 6.02 (s,1H, OH), 6.44 (m, 2H), 7.20-7.40 (m, 5H), 7.63 (m, 1H).

Example 67(3R)-3-[(2R)-2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 64. The yield of thefinal step was 10 mg, 38%.

MS [M-CF₃COO]⁺: 438

¹H-NMR (DMSO-d₆): δ 1.40-1.60 (m, 8H), 1.75-2.05 (m, 6H), 2.27 (m, 1H),2.55-2.60 (m, 2H), 2.79 (m, 1H), 3.04-3.10 (m, 1H), 3.12-3.40 (m, 5H),3.40-3.52 (m, 1H), 3.80-3.90 (m, 1H), 5.10 (m, 1H), 6.02 (s, 1H, OH),6.40 (m, 2H), 7.20-7.35 (m, 5H), 7.58 (m, 1H)

Example 68(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised according to methods d, and b fromthe Intermediate I-16a. The yield of the final step was 28 mg, 100%.

MS [M-CF₃COO]⁺: 478.

¹H-NMR (DMSO-d₆): δ 0.95-1.18 (m, 4H), 1.18-1.65 (m, 5H), 1.70-2.05 (m,5H), 2.05-2.17 (m, 2H), 2.17-2.30 (m, 2H), 3.15-3.25 (m, 1H), 3.25-3.55(m, 6H), 3.75-3.90 (m, 1H), 3.95-4.07 (m, 2H), 5.05-5.15 (m, 1H), 5.78(s, 1H, OH), 6.90-7.0 (m, 3H), 7.25-7.45 (m, 5H), 7.55-7.65 (m, 2H).

Example 69(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 68. The yield of thefinal step was 22 mg, 78%.

MS [M-CF₃COO]⁺: 468.

¹H-NMR (DMSO-d₆): δ 0.95-1.18 (m, 4H), 1.18-1.65 (m, 5H), 1.70-2.0 (m,7H), 2.20 (m, 2H), 2.75-2.85 (m, 2H), 3.05-3.15 (m, 1H), 3.15-3.50 (m,6H), 3.70-3.85 (m, 1H), 5.05-5.15 (m, 1H), 5.76 (s, 1H, OH), 6.90-7.05(m, 2H), 7.20-7.45 (m, 4H), 7.55-7.65 (m, 2H)

Example 70(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 68. The yield of thefinal step was 14 mg, 50%.

MS [M-CF₃COO]⁺: 448.

¹H-NMR (DMSO-d₆): δ 0.97-1.15 (m, 3H), 1.15-2.05 (m, 11H), 2.15-2.30 (m,2H), 2.90-3.05 (m, 2H), 3.20-3.30 (m, 1H), 3.30-3.50 (m, 5H), 3.50-3.62(m, 1H), 3.82-3.92 (m, 1H), 5.15 (m, 1H), 5.78 (s, 1H, OH), 7.25-7.45(m, 8H), 7.58-7.64 (m, 2H).

Example 71(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised according to methods d, and b fromthe Intermediate I-16b. The yield of the final step was 18 mg, 63%.

MS [M-CF₃COO]⁺: 478.

¹H-NMR (DMSO-d₆): δ 0.95-1.17 (m, 4H), 1.20-2.0 (m, 10H), 2.02-2.35 (m,4H), 3.15-3.55 (m, 7H), 3.80-3.90 (m, 1H), 3.97-4.10 (m, 2H), 5.05-5.15(m, 1H), 5.75 (s, 1H, OH), 6.90-7.02 (m, 3H), 7.25-7.45 (m, 5H),7.57-7.67 (m, 2H)

Example 72(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 71. The yield of thefinal step was 19 mg, 66%.

MS [M-CF₃COO]⁺: 468.

¹H-NMR (DMSO-d₆): δ 0.95-1.17 (m, 4H), 1.20-2.10 (m, 12H), 2.15-2.35 (m,2H), 2.75-2.97 (m, 2H), 3.10-3.37 (m, 6H), 3.37-3.55 (m, 1H), 3.75-3.87(m, 1H), 5.05-5.12 (m, 1H), 5.74 (s, 1H, OH), 6.90-7.05 (m, 2H),7.22-7.45 (m, 4H), 7.55-7.67 (m, 2H).

Example 73(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 71. The yield of thefinal step was 16 mg, 58%.

MS [M-CF₃COO]⁺: 448.

¹H-NMR (DMSO-d₆): δ 0.98-1.15 (m, 3H), 1.20-2.05 (m, 11H), 2.20-2.35 (m,2H), 2.90-3.10 (m, 2H), 3.20-3.50 (m, 6H), 3.50-3.60 (m, 1H), 3.80-3.92(m, 1H), 5.12 (m, 1H), 5.75 (s, 1H, OH), 7.25-7.40 (m, 8H), 7.60-7.65(m, 1H).

Example 74(3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised according to methods c, and b fromthe intermediate I-4a. The yield of the final step was 3.8 mg, 6.2%.

MS [M-CF₃COO]⁺: 468.

¹H-NMR (DMSO-d₆): δ 1.0-1.50 (m, 7H), 1.50-2.05 (m, 7H), 2.05-2.35 (m,4H), 3.15-3.65 (m, 7H), 3.82-3.95 (m, 1H), 4.0-4.1 (m, 2H), 5.16 (m,1H), 5.99 (s, 1H, OH), 6.40-6.45 (m, 2H), 6.90-7.0 (m, 3H), 7.25-7.35(m, 2H), 7.64 (m, 1H).

Example 75(3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 74. The yield of thefinal step was 3.6 mg, 6%.

MS [M-CF₃COO]⁺: 458.

¹H-NMR (DMSO-d₆): δ 1.0-1.45 (m, 7H), 1.50-2.10 (m, 9H), 2.15-2.30 (m,2H), 2.75-2.90 (m, 2H), 3.10-3.55 (m, 7H), 3.77-3.92 (m, 1H), 5.13 (m,1H), 5.98 (s, 1H, OH), 6.36-6.46 (m, 2H), 6.92-7.02 (m, 2H), 7.36-7.40(m, 1H), 7.62 (m, 1H).

Example 76(3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 74. The yield of thefinal step was 2.4 mg, 4.2%.

MS [M-CF₃COO]⁺: 438.

¹H-NMR (DMSO-d₆): δ 1.0-1.45 (m, 7H), 1.50-2.05 (m, 7H), 2.20-2.35 (m,2H), 2.92-3.15 (m, 2H), 3.20-3.65 (m, 7H), 3.85-3.95 (m, 1H), 5.18 (m,1H), 6.0 (s, 1H, OH), 6.37-6.47 (m, 2H), 7.25-7.45 (m, 5H), 7.64 (m,1H).

Example 77(3R)-3-[(2S)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 74. The yield of thefinal step was 2.8 mg, 4.8%.

MS [M-CF₃COO]⁺: 452.

¹H-NMR (DMSO-d₆): δ 0.95-1.50 (m, 7H), 1.50-2.10 (m, 9H), 2.15-2.32 (m,2H), 2.55-2.65 (m, 2H), 3.10-3.60 (m, 7H), 3.77-3.80 (m, 1H), 5.12 (m,1H), 5.98 (s, 1H, OH), 6.36-6.46 (m, 2H), 7.18-7.40 (m, 5H), 7.62 (m,1H).

Example 78(3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised according to methods c, and b fromthe Intermediate I-4b. The yield of the final step was 3.0 mg, 5%.

MS [M-CF₃COO]⁺: 468.

¹H-NMR (DMSO-d₆): δ 1.0-1.45 (m, 7H), 1.55-1.75 (m, 3H), 1.80-2.05 (m,4H), 2.05-2.25 (m, 3H), 2.30 (m, 1H), 3.10-3.20 (m, 1H), 3.20-3.60 (m,6H), 3.85-3.95 (m, 1H), 3.95-4.10 (m, 2H), 5.16 (m, 1H), 5.99 (s, 1H,OH), 6.40-6.50 (m, 2H), 6.90-7.0 (m, 3H), 7.25-7.38 (m, 2H), 7.64 (m,1H).

Example 79(3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 78. The yield of thefinal step was 9.1 mg, 33.1%.

MS [M-CF₃COO]⁺: 458.

¹H-NMR (DMSO-d₆): δ 0.95-1.55 (m, 7H), 1.55-2.10 (m, 9H), 2.10-2.40 (m,2H), 2.75-2.95 (m, 2H), 3.0-3.12 (m, 1H), 3.12-3.70 (m, 6H), 3.80-3.95(m, 1H), 5.14 (m, 1H), 6.0 (s, 1H, OH), 6.35-6.55 (m, 2H), 6.90-7.10 (m,2H), 7.35-7.45 (m, 1H), 7.60-7.70 (m, 1H).

Example 80(3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 78. The yield of thefinal step was 3.6 mg, 6%.

MS [M-CF₃COO]⁺: 438.

¹H-NMR (DMSO-d₆): δ 1.0-1.45 (m, 7H), 1.55-1.80 (m, 3H), 1.80-2.10 (m,4H), 2.12-2.28 (m, 1H), 2.30 (m, 1H), 2.90-3.05 (m, 2H), 3.15-3.25 (m,1H), 3.25-3.50 (m, 5H), 3.50-3.65 (m, 1H), 3.85-3.95 (m, 1H), 5.18 (m,1H), 6.0 (s, 1H, OH), 6.38-6.48 (m, 2H), 7.24-7.40 (m, 5H), 7.65 (m,1H).

Example 81(3R)-3-[(2R)-2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 78. The yield of thefinal step was 5.8 mg, 10%.

MS [M-CF₃COO]⁺: 452.

¹H-NMR (DMSO-d₆): δ 1.0-1.42 (m, 7H), 1.55-1.77 (m, 3H), 1.77-2.05 (m,6H), 2.18 (m, 1H), 2.27 (m, 1H), 2.55-2.65 (m, 2H), 3.02-3.12 (m, 1H),3.12-3.60 (m, 6H), 3.77-3.90 (m, 1H), 5.13 (m, 1H), 5.98 (s, 1H, OH),6.40 (m, 2H), 7.20-7.35 (m, 5H), 7.61 (m, 1H).

Example 82(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised according to methods c, and b fromIntermediate I-5a. The yield of the final step was 9.4 mg, 15.6%.

MS [M-CF₃COO]⁺: 464

¹H-NMR (DMSO-d₆): δ 1.10-1.70 (m, 8H), 1.70-2.02 (m, 4H), 2.05-2.15 (m,2H), 2.24 (m, 1H), 2.90-2.97 (m, 1H), 3.15-3.25 (m, 1H), 3.25-3.60 (m,6H), 3.75-3.92 (m, 1H), 3.95-4.10 (m, 2H), 5.10 (m, 1H), 5.86 (s, 1H,OH), 6.90-7.0 (m, 3H), 7.20-7.40 (m, 5H), 7.56-7.66 (m, 2H).

Example 83(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 82. The yield of thefinal step was 5.0 mg, 8.8%.

MS [M-CF₃COO]⁺: 434

¹H-NMR (DMSO-d₆): δ 1.12-1.70 (m, 8H), 1.75-2.05 (m, 4H), 2.26 (m, 1H),2.87-3.05 (m, 3H), 3.15-3.62 (m, 7H), 3.80-3.92 (m, 1H), 5.13 (m, 1H),5.86 (s, 1H, OH), 7.24-7.44 (m 8H), 7.56-7.66 (m, 2H).

Example 84(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 82. The yield of thefinal step was 3.2 mg, 5.1%.

MS [M-CF₃COO]⁺: 480

¹H-NMR (DMSO-d₆): δ 1.12-1.65 (m, 8H), 1.65-2.0 (m, 6H), 2.21 (m, 1H),2.85-3.15 (m, 4H), 3.15-3.55 (m, 6H), 3.70-3.85 (m, 1H), 5.06 (m, 1H),5.83 (s, 1H, OH), 7.20-7.46 (m, 8H), 7.54-7.64 (m, 2H).

Example 85(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised according to methods c, and b fromIntermediate I-5b. The yield of the final step was 7.8 mg, 12.9%.

MS [M-CF₃COO]⁺: 464

¹H-NMR (DMSO-d₆): δ 1.15-1.35 (m, 2H), 1.35-2.0 (m, 10H), 2.0-2.30 (m,3H), 2.95-3.10 (m, 1H), 3.20-3.60 (m, 7H), 3.80-3.95 (m, 1H), 3.97-4.10(m, 2H), 5.09 (m, 1H), 5.84 (s, 1H, OH), 6.90-7.0 (m, 3H), 7.24-7.44 (m,5H), 7.60-7.70 (m, 2H).

Example 86(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 85. The yield of thefinal step was 5.2 mg, 9.2%.

MS [M-CF₃COO]⁺: 434

¹H-NMR (DMSO-d₆): δ 1.12-1.32 (m, 2H), 1.32-2.05 (m, 10H), 2.20 (m, 1H),2.90-3.10 (m, 3H), 3.20-3.62 (m, 7H), 3.82-3.97 (m, 1H), 5.12 (m, 1H),5.85 (s, 1H, OH), 7.22-7.45 (m, 8H), 7.60-7.70 (m, 2H).

Example 87(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 85. The yield of thefinal step was 4.0 mg, 6.4%.

MS [M-CF₃COO]⁺: 480

¹H-NMR (DMSO-d₆): δ 1.12-1.32 (m, 2H), 1.32-1.70 (m, 8H), 1.70-2.0 (m,4H), 2.16 (m, 1H), 2.92-3.05 (m, 3H), 3.15-3.60 (m, 7H), 3.75-3.87 (m,1H), 5.04 (m, 1H), 5.82 (s, 1H, OH), 7.20-7.44 (m, 8H), 7.58-7.68 (m,2H).

Example 88(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised according to methods c, and b fromintermediate I-6a. The yield of the final step was 3.2 mg, 5.1%.

MS [M-CF₃COO]⁺: 484

¹H-NMR (DMSO-d₆): δ 1.0-1.45 (m, 7H), 1.55-1.80 (m, 3H), 1.80-2.20 (m,7H), 2.25-2.35 (m, 1H), 3.20-3.28 (m, 1H), 3.28-3.42 (m, 5H), 3.42-3.55(m, 1H), 3.85-3.95 (m, 1H), 4.01-4.05 (m, 2H), 5.17 (m, 1H), 6.16 (s,1H, OH), 6.92-7.03 (m, 4H), 7.13-7.15 (m, 1H), 7.28-7.34 (m, 2H),7.42-7.45 (m, 1H).

Example 89(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 88. The yield of thefinal step was 3.4 mg, 5.8%.

MS [M-CF₃COO]⁺: 454

¹H-NMR (DMSO-d₆): δ 1.0-1.45 (m, 7H), 1.55-1.80 (m, 3H), 1.80-2.15 (m,5H), 2.32 (m, 1H), 2.95-3.05 (m, 2H), 3.20-3.52 (m, 6H), 3.52-3.68 (m,1H), 3.85-3.95 (m, 1H), 5.20 (m, 1H), 6.16 (s, 1H, OH), 7.0-7.04 (m,1H), 7.10-7.15 (m, 1H), 7.25-7.40 (m, 5H), 7.43-7.46 (m, 1H).

Example 901-[3-(3-Cyanophenoxy)propyl]-(3R)-3-[(2S)-2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 88. The yield of thefinal step was 8.4 mg, 12.7%.

MS [M-CF₃COO]⁺: 509

¹H-NMR (DMSO-d₆): δ 1.0-1.45 (m, 7H), 1.55-1.70 (m, 3H), 1.70-2.20 (m,7H), 2.31 (m, 1H), 3.20-3.27 (m, 1H), 3.25-3.50 (m, 5H), 3.45-3.60 (m,1H), 3.85-3.95 (m, 1H), 4.05-4.15 (m, 2H), 5.18 (m, 1H), 6.16 (s, 1H,OH), 7.0-7.03 (m, 1H), 7.13-7.15 (m, 1H), 7.28-7.31 (m, 1H), 7.43-7.46(m, 3H), 7.50-7.55 (m, 1H).

Example 91(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised according to methods c, and b fromIntermediate I-6b (The Intermediate I-6b used herein contains approx.25% of I-6a, see previous description in method c). The yield of thefinal step was 3.0 mg, 4.8%.

MS [M-CF₃COO]⁺: 484

¹H-NMR (DMSO-d₆): δ 1.0-1.50 (m, 7H), 1.55-2.22 (m, 10H), 2.25-2.35 (m,1H), 3.20-3.45 (m, 5H), 3.45-3.60 (m, 1H), 3.85-3.95 (m, 1H), 4.0-4.10(m, 2H), 5.17 (m, 1H), 6.14 (and 6.16) (s, 1H, OH, mixture ofdiastereomers approx. 75:25), 6.93-7.03 (m, 4H), 7.13-7.17 (m, 1H),7.28-7.35 (m, 2H), 7.42-7.45 (m, 1H).

Example 92(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 91. The yield of thefinal step was 2.6 mg, 4.4%.

MS [M-CF₃COO]⁺: 454

¹H-NMR (DMSO-d₆): δ 1.50-1.70 (m, 7H), 1.55-2.20 (m, 8H), 2.28 (m, 1H),2.95-3.10 (m, 2H), 3.20-3.52 (m, 6H), 3.52-3.65 (m, 1H), 3.85-3.97 (m,1H), 5.15-5.25 (m, 1H), 6.14 (and 6.16), (s, 1H, OH, mixture ofdiastereomers approx. 75:25), 6.98-7.04 (m, 1H), 7.13-7.16 (m, 1H),7.25-7.40 (m, 5H), 7.43-7.46 (m, 1H).

Example 931-[3-(3-Cyanophenoxy)propyl]-(3R)-3-[(2R)-2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy]-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 91. The yield of thefinal step was 5.0 mg, 7.5%.

MS [M-CF₃COO]⁺: 509

¹H-NMR (DMSO-d₆): δ 1.0-1.50 (m, 7H), 1.55-2.05 (m, 7H), 2.05-2.22 (m,3H), 2.22-2.35 (m, 1H), 3.20-3.50 (m, 6H), 3.45-3.60 (m, 1H), 3.80-3.95(m, 1H), 4.10-4.15 (m, 2H), 5.17 (m, 1H), 6.14 (and 6.16) (s, 1H, OH,mixture of diastereomers approx. 75:25), 7.0-7.03 (m, 1H), 7.13-7.16 (m,1H), 7.28-7.32 (m, 1H), 7.43-7.46 (m, 3H), 7.50-7.55 (m, 1H).

Example 94(3R)-3-(2-Hydroxy-4-phenyl-2-thien-2-ylbutanoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as a mixture of diastereomersaccording to methods d, and b from Intermediate I-21. The yield of thefinal step was 4.8 mg, 15.8%.

MS [M-CF₃COO]⁺: 506

¹H-NMR (DMSO-d₆): δ 1.75-2.05 (m, 3H), 2.05-2.20 (m, 2H), 2.20-2.35 (m,2H), 2.37-2.70 (m, 4H), 3.20-3.65 (m, 7H), 3.82-3.95 (m, 1H), 4.0-4.1(m, 2H), 5.12 (m, 1H), 6.58 (s, 1H, OH), 6.90-7.0 (m, 3H), 7.0-7.08 (m,1H), 7.14-7.24 (m, 4H), 7.24-7.36 (m, 4H), 7.46-7.52 (m, 1H).

Example 95(3S)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide

The title compound was synthesised according to methods, c, and a fromthe Intermediate I-7. The yield of the final step was 250 mg, 87.1%.

MS [M-Br]⁺: 470

¹H-NMR (DMSO-d₆): δ (Same description as in Example 53)

Example 96(3S)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised according to methods c, and b fromthe Intermediate I-7. The yield of the final step was 11.1 mg, 40.2%.

MS [M-CF₃COO]⁺: 460

¹H-NMR (DMSO-d₆): δ (Same description as in Example 54)

Example 97(3S)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 96. The yield of thefinal step was 11.3 mg, 41.4%.

MS [M-CF₃COO]⁺: 454.

¹H-NMR (DMSO-d₆): δ (Same description as in Example 57).

Example 984-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised according to methods c, and b fromthe Intermediate I-8. The yield was 9.4 mg, 34.6%.

MS [M-CF₃COO]⁺: 468

¹H-NMR (DMSO-d₆): δ 0.90-1.65 (m, 9H), 1.70-1.80 (m, 1H), 1.90-2.05 (m,2H), 2.05-2.20 (m, 1H), 2.18-2.35 (m, 6H), 2.75-2.90 (m, 2H), 3.10-3.25(m, 2H), 3.45-3.70 (m, 6H), 5.60 (s, 1H, OH), 6.90-6.92 (m, 1H),6.95-7.02 (m, 1H), 7.20-7.45 (m, 4H), 7.50-7.60 (m, 2H).

Example 994-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate

The title compound was synthesised as in Example 98. The yield of thefinal step was 8.1 mg, 29.2%.

MS [M-CF₃COO]⁺: 478

¹H-NMR (DMSO-d₆): δ 0.90-1.65 (m, 9H), 1.70-1.80 (m, 1H), 2.05-2.20 (m,3H), 2.20-2.40 (m, 6H), 3.20-3.45 (m, 2H), 3.50-3.75 (m, 6H), 3.95-4.10(m, 2H), 5.60 (s, 1H, OH), 6.85-7.05 (m, 3H), 7.20-7.45 (m, 5H),7.50-7.65 (m, 2H).

((*): Configuration not assigned)

The following examples illustrate pharmaceutical compositions accordingto the present invention and procedures for their preparation.

Example 100 Preparation of a Pharmaceutical Composition Tablets

Formulation:

Compound of the present invention 5.0 mg Lactose 113.6 mg Microcrystalline cellulose 28.4 mg  Light silicic anhydride 1.5 mgMagnesium stearate 1.5 mg

Using a mixer machine, 15 g of the compound of the present invention wasmixed with 340.8 g of lactose and 85.2 g of microcrystalline cellulose.The mixture was subjected to compression moulding using a rollercompactor to give a flake-like compressed material. The flake-likecompressed material was pulverized using a hammer mill, and thepulverized material was screened through a 20 mesh screen. A 4.5 gportion of light silicic anhydride and 4.5 g of magnesium stearate wereadded to the screened material and mixed. The mixer product wassubjected to a tablets making machine equipped with a die/punch systemof 7.5 mm in diameter, thereby obtaining 3,000 tablets each having 150mg in weight.

Example 101 Preparation of a Pharmaceutical Composition Tablets Coated

Formulation:

Compound of the present invention 5.0 mg Lactose 95.2 mg  Corn starch40.8 mg  Polyvinylpyrrolidone K25 7.5 mg Magnesium stearate 1.5 mgHydroxypropylcellulose 2.3 mg Polyethylene glycol 6000 0.4 mg Titaniumdioxide 1.1 mg Purified talc 0.7 mg

Using a fluidized bed granulating machine, 15 g of the compound of thepresent invention was mixed with 285.6 g of lactose and 122.4 g of cornstarch. Separately, 22.5 g of polyvinylpyrrolidone was dissolved in127.5 g of water to prepare a binding solution. Using a fluidized bedgranulating machine, the binding solution was sprayed on the abovemixture to give granulates. A 4.5 g portion of magnesium stearate wasadded to the obtained granulates and mixed. The obtained mixture wassubjected to a tablet making machine equipped with a die/punch biconcavesystem of 6.5 mm in diameter, thereby obtaining 3,000 tablets, eachhaving 150 mg in weight.

Separately, a coating solution was prepared by suspending 6.9 g ofhydroxypropylmethylcellulose 2910, 1.2 g of polyethylene glycol 6000,3.3 g of titanium dioxide and 2.1 g of purified talc in 72.6 g of water.Using a High Coated, the 3,000 tablets prepared above were coated withthe coating solution to give film-coated tablets, each having 154.5 mgin weight.

Example 102 Preparation of a Pharmaceutical Composition Liquid Inhalant

Formulation:

Compound of the present invention 400 μg Physiological saline  1 ml

A 40 mg portion of the compound of the present invention was dissolvedin 90 ml of physiological saline, and the solution was adjusted to atotal volume of 100 ml with the same saline solution, dispensed in 1 mlportions into 1 ml capacity ampoule and then sterilized at 115° for 30minutes to give liquid inhalant.

Example 103 Preparation of a Pharmaceutical Composition Powder Inhalant

Formulation:

Compound of the present invention   200 μg Lactose 4,000 μg

A 20 g portion of the compound of the present invention was uniformlymixed with 400 g of lactose, and a 200 mg portion of the mixture waspacked in a powder inhaler for exclusive use to produce a powderinhalant.

Example 104 Preparation of a Pharmaceutical Composition InhalationAerosol

Formulation:

Compound of the present invention   200 μg Dehydrated (Absolute) ethylalcohol USP  8,400 μg 1,1,1,2-Tetrafluoroethane (HFC-134A) 46,810 μg

The active ingredient concentrate is prepared by dissolving 0.0480 g ofthe compound of the present invention in 2.0160 g of ethyl alcohol. Theconcentrate is added to an appropriate filling apparatus The activeingredient concentrate is dispensed into aerosol container, theheadspace of the container is purged with Nitrogen or HFC-134A vapor(purging ingredients should not contain more than 1 ppm oxygen) and issealed with valve. 11.2344 g of HFC-134A propellant is then pressurefilled into the sealed container.

1. A compound of formula (I):

wherein either (a) B is a phenyl, thienyl or furyl ring and p represents2, or (b) B is a phenyl ring and p represents 1; R¹, R² and R³ eachindependently represent a hydrogen or halogen atom, or a phenyl group,—OR⁷, —SR⁷, —NR⁷R⁸, —NHCOR⁷, —CONR⁷R⁸, —CN, —NO₂, —COOR⁷ or —CF₃ group,or a straight or branched, substituted or unsubstituted lower alkylgroup, wherein R⁷ and R⁸ each independently represent a hydrogen atom, astraight or branched lower alkyl group; n is an integer from 0 to 4; Arepresents a group selected from —CH₂—, —CH═R⁹—, —CR⁹═CH—, —CO—, —O—,—S—, —S(O)—, —S(O)₂— and —NR⁹—, wherein R⁹ and R¹⁰ each independentlyrepresent a hydrogen atom, a straight or branched lower alkyl group; mis an integer from 0 to 8, provided that when m=0, A is not —CH₂—; thesubstitution in the azoniabicyclic ring may be in the 2, 3 or 4 positionincluding all possible configurations of the asymmetric carbons; R⁴represents the structure:

wherein R¹¹ represents a hydrogen or halogen atom, a hydroxy group, analkoxy group, a nitro group, a cyano group, —CO₂R¹² or —NR¹²R¹³, whereinR¹² and R¹³ are identical or different and are selected from hydrogenand straight or branched lower alkyl groups, or a straight or branched,substituted or unsubstituted lower alkyl group; R⁵ represents an alkylgroup of 1 to 7 carbon atoms, an alkenyl group containing 2 to 7 carbonatoms, an alkynyl group containing 2 to 7 carbon atoms, a cycloalkylgroup of 3 to 7 carbon atoms, or a group of formula

wherein q=1 or 2 and R¹⁴ represents a hydrogen or halogen atom, ahydroxy group, an alkoxy group, a nitro group, a cyano group, —CO₂R¹² or—NR¹²R¹³, wherein R¹² and R¹³ are identical or different and areselected from hydrogen and straight or branched lower alkyl groups, or astraight or branched, substituted or unsubstituted lower alkyl group; R⁶represents a hydrogen atom, a hydroxy group, a methyl group or a —CH₂OHgroup; and X⁻ represents a pharmaceutically acceptable anion of a monoor polyvalent acid.
 2. A compound according to claim 1 wherein R⁴represents an unsubstituted phenyl group.
 3. A compound according toclaim 1, wherein R⁵ represents a cyclopentyl, cyclohexyl, pentyl, allyl,vinyl, propynyl, benzyl or phenethyl group.
 4. A compound according toclaim 1 wherein the group —O—CO—C(R⁴)(R⁵)(R⁶) represents a groupselected from 2,3-diphenylpropionyloxy;2-hydroxymethyl-2,3-diphenylpropionyloxy;2-hydroxy-2,3-diphenylpropionyloxy;2-cyclohexyl-2-hydroxy-2-phenylacetoxy and2-cyclopentyl-2-hydroxy-2-phenylacetoxy.
 5. A compound according toclaim 1 wherein R¹, R² and R³ each independently represent a hydrogen orhalogen atom or a hydroxy, methyl, tert-butyl, —CH₂OH, 3-hydroxypropyl,—OMe, —NMe₂-NHCOMe, —CONH₂, —CN, —NO₂, —COOMe or —CF₃ group.
 6. Acompound according to claim 5 wherein R¹, R² and R³ each independentlyrepresent a hydrogen or halogen atom or a hydroxy group.
 7. A compoundaccording to claim 1, wherein n=0 or 1; m is an integer from 1 to 6; andA represents a —CH₂—, —CH═CH—, —CO—, —NMe-, —O— or —S— group.
 8. Acompound according to claim 7, wherein m is 1, 2 or 3 and A represents a—CH₂—, —CH═CH—, —O— or —S— group.
 9. A compound according to claim 1,wherein the azoniabicyclo group is substituted on the nitrogen atom witha group selected from 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl,phenethyl, 3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl,3-(4-fluorophenoxy)propyl, 3-thien-2-ylpropyl, 4-oxo-4-thien-2-ylbutyl,2-benzyloxyethyl, 3-o-tolyloxypropyl, 3-(3-cyanophenoxy)propyl,3-(methylphenylamino)propyl, 3-phenylsulfanylpropyl,4-oxo-4-phenylbutyl, 3-(2-chlorophenoxy)propyl,3-(2,4-difluorophenoxy)propyl, and 3-(4-methoxyphenoxy)propyl.
 10. Acompound according to claim 1, wherein X⁻ represents a chloride,bromide, trifluoroacetate or methanesulphonate anion.
 11. A compoundaccording to claim 1, wherein the azoniabicyclic group is substituted inthe 3-position.
 12. A compound according to claim 11, wherein thesubstituent at the 3-position of the azoniabicyclic group has Rconfiguration.
 13. A compound according to claim 11, wherein thesubstituent at the 3-position of the azoniabicyclic group has Sconfiguration.
 14. A compound according to claim 1, wherein the carbonsubstituted by R⁴, R⁵ and R⁶ has R configuration.
 15. A compoundaccording to claim 1 wherein the carbon substituted by R⁴, R⁵ and R⁶ hasS configuration.
 16. A compound according to claim 1, which is presentsubstantially as a single isomer.
 17. A compound according to claim 1which is:(3R)-3-(2,3-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2,3-Diphenylpropionyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2-Hydroxymethyl-2,3-diphenylpropionyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2-Hydroxymethyl-2,3-diphenylpropionyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-(2-Hydroxy-2,3-diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-(2-Hydroxy-2,3-diphenylpropionyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octanebromide(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octanetrifluoroacetate(3R)-3-[(2S)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate4-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate4-[(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate.
 18. A process for producing a compound of formula (I):as defined in claim 1, which process comprises quaternising the nitrogenatom of the azabicyclic ring of a compound of formula (III):

wherein R⁴, R⁵, R⁶ and p are as defined in claim 1, with an alkylatingagent of formula

wherein R¹, R², R³, m, n, A and B are as defined in claim 1, and Wrepresents a leaving group.
 19. A process according to claim 18, whereinW represents a group X, wherein X represents a pharmaceuticallyacceptable anion of a mono or polyvalent acid.
 20. A process accordingto claim 18 further comprising the step of purifying the reactionmixture by solid phase extraction.
 21. A pharmaceutical compositioncomprising a compound according to claim 1 in admixture with apharmaceutically acceptable carrier or diluent.
 22. A compound accordingto claim 1, wherein each lower alkyl group is a C₁-C₈ group.
 23. Acompound according to claim 1, wherein said substituted lower alkylgroup is a C₁-C₈ alkyl group substituted by 1, 2 or 3 substituentsselected from halogen atoms and hydroxyl and C₁-C₆ alkoxy groups.